Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains (Review)

  • Authors:
    • Yiying Song
    • Haiting Liu
    • Qingqing Xian
    • Chengzhi Gui
    • Mingjie Xu
    • Yunying Zhou
  • View Affiliations

  • Published online on: November 2, 2023
  • Article Number: 542
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Epigenetic modification is crucial for transmitting genetic information, while abnormalities in DNA methylation modification are primarily associated with cancer and neurological diseases. As a multifunctional epigenetic modifier, ubiquitin like with PHD and ring finger domains 1 (UHRF1) mainly affects cell energy metabolism and cell cycle control. It also inhibits the transcription of tumor suppressor genes through DNA and/or histone methylation modifications, promoting the occurrence and development of cancer. Therefore, comprehensively understanding the molecular mechanism of the epigenetic modification of UHRF1 in tumors will help identify targets for inhibiting the expression and function of UHRF1. Notably, each domain of UHRF1 functions as a whole and differently. Thus, the abnormality of any domain can lead to a change in phenotype or disease. However, the specific regulatory mechanism and proteins of each domain have not been fully elucidated. The present review aimed to contribute to the study of the regulatory mechanism of UHRF1 to a greater extent in different cancers and provide ideas for drug research by clarifying the function of UHRF1 domains.


During tumorigenesis, abnormalities in key genes and/or epigenetic events always occur in cell metabolism, survival and proliferation. Epigenetic modification refers to genetic changes in gene expression without altering the structure or sequence of DNA. This includes DNA methylation, histone modification, genomic imprinting, X chromosome inactivation and microRNA regulation (1). Among these, DNA methylation and histone modification are the most significant (2). DNA methylation is the process of transferring the methyl group to the C5 position of cytosine to form 5-methylcytosine (5mC). This process typically inhibits gene expression (3). DNA methylation includes two forms: de novo methylation and maintenance methylation or hemimethylation. Complete DNA methylation involves three aspects: Recognition, establishment and removal, and requires the cooperation of three molecules (writer, eraser and reader). A number of studies have revealed that ubiquitin like with PHD and ring finger domains 1 (UHRF1) is involved in both de novo methylation and maintenance methylation, which is mainly used as a reader to identify the DNA to be methylated and then recruits writers to complete DNA methylation (4), thus inhibiting transcription.

The methylation effect of UHRF1 varies in different types of cancer. DNA methylation of cancer cells (such as non-small cell lung cancer, malignant pleural mesothelioma, endometrial cancer and liver cancer) can be induced by UHRF1 (59). By contrast, DNA methylation can also be inhibited by UHRF1 in esophageal squamous cell carcinoma and glioma (10,11). Additionally, UHRF1 has little effect on DNA methylation in retinoblastoma (12). Moreover, a number of studies have reported that UHRF1 is involved in the proliferation of Treg cells (13) and adult vascular smooth muscle cells by methylating promoters of cyclin-dependent kinase suppressor genes (including P21 and P27) (14). It has been revealed that the overexpression of UHRF1 is related to the hypermethylation of tumor suppressor genes (TSGs) in numerous cancers (1521). In addition to affecting TSGs, UHRF1 can also affect cancer progression in immune, proliferative, apoptosis (including ferroptosis) (22), and other aspects through epigenetic modifications to proteins. A recent study indicated that UHRF1 can affect the immune ability of interferon against tumors by affecting the methylation of cyclic GMP AMP synapse (23). Currently, testing all-natural anticancer compounds involves the downregulation of UHRF1 and the upregulation of TSG expression (2428). However, numerous regulatory functions of UHRF1 involved in regulation have not been thoroughly studied. Therefore, understanding the molecular mechanism of the epigenetic modification of UHRF1 in tumors will help identify targets for the inhibition of the expression and function of UHRF1, which could thus play an anticancer role.

Generally, the clinical significance of UHRF1 has two aspects. First, it can improve the prognosis and survival rate as a therapeutic target for radiotherapy and chemotherapy (29). Second, it can serve as an effective biomarker for diagnosis, prognosis and survival rate. The present review aimed to comprehensively summarize the role of UHRF1 in DNA methylation by clarifying the functions of its domains to provide convenience for further exploration and clinical treatment of cancers in the future.

Structure of UHRF1

UHRF1 is a 90 kDa reverse CCAAT box-binding protein (ICBP90). The UHRF1 gene consists of 59,075 bases on chromosome 19 (19p13.3). UHRF1 has five main functional domains (Fig. 1): i) N-terminal ubiquitin-like domain (UBL), ii) tandem Tudor domain (TTD), iii) plant homeodomain (PHD), iv) set and ring-associated domain (SRA) and v) really interesting new gene domain (RING) (30). In the methylation process of UHRF1, each domain plays a crucial role. Abnormality in any domain may cause abnormal function of UHRF1, resulting in disease occurrence or phenotypic changes. It has been reported that the PHD and SRA domains are necessary for the maintenance of UHRF1-dependent DNA methylation through mutation of different domains of UHRF1 (31). In addition to methylation, UHRF1 interacts with various proteins, including DNA methyltransferases 1 (DNMT1), herpes virus-associated ubiquitin-specific protease (HAUSP), histone deacetylase 1 (HDAC1), Tip60, heat shock protein 90α family (HSP90), SUV39H1 histone lysine methyltransferase (SUV39H1), proliferating cell nuclear antigen (PCNA) and retinoblastoma gene product (pRb). A macromolecular protein complex called ‘epigenetic code replication machinery (ECReM)’ is formed through these domains. This complex interacts with each other and participates in the transmission of the epigenetic codes (32).

Role and characteristics of UHRF1 domains in DNA methylation

DNA methylation mainly occurs on the 5′-carbon in the cytosine of cytosine-phosphate-guanine (CpG) dinucleotide (33), which varies greatly in different human tissues (34). The maintenance of methylation can be divided into two stages. The first stage is the rapid replication-coupling stage, which occurs within a few min after DNA double-strand bifurcation. This stage is responsible for maintaining more than 80% of hemimethylation. The other is the relatively slow replication-uncoupling stage that occurs later (35), with UHRF1 and DNMT1 involved. This stage mainly consists of five steps and two conformations (Fig. 2).

Step 1

At first, UHRF1 is in a closed conformation: SRA combines with PHD. The diversity region (PBR) between SRA and RING binds to TTD competitively with the linker (but mainly PBR), thus preventing TTD from binding to H3k9me3. However, this state does not hinder the interaction along UBL, RING, and ubiquitin-binding enzyme (E2)-ubiquitin molecules (36).

Step 2

UHRF1 undergoes a conformational change from a closed state to an open conformation in the following three scenarios: i) HAUSP binds to PBR of UHRF1 and hemi-methylated DNA (hmDNA; where only one of the two complementary strands is methylated); ii) SRA binds to hmDNA and iii) phosphorylation of S651 by phosphatidyl-5-phosphate (PI5P) leads to the release of the PBR's binding to TTD, allowing TTD to bind histone with the PHD domain and linker (37). Since the concentration of PI5P is different in the G1 and S phases, the localization of UHRF1 in chromatin in the cell cycle can be determined by analyzing the concentration of PI5P (38).

Step 3

In the open state, TTD-PHD binds to H3K9me2/3, UBL and histone H3 ubiquitinated by RING, and then UHRF1 recruits DNMT1 (39) in a cell cycle-dependent manner (4042) and relieves the autoinhibitory activity of DNMT1 (37). In addition, UBL and SRA also recruit DNMT1, releasing its catalytic domain. Moreover, H3K27me3 can affect DNA methylation by inhibiting UHRF1-mediated H3 ubiquitination in this process (43).

Step 4

The binding of the replication foci targeting (RFT) domain of DNMT1 with two monoubiquitinated histones H3 disrupts the interaction between RFT and its C-terminal catalytic domain, resulting in the conformational change of DNMT1, allowing hmDNA to enter the catalytic center and undergo DNA methylation. It is also considered that DNMT1 is unlikely to dissociate and bind repeatedly from UHRF1 or the UHRF1 complex during methylation modification of multiple methylation sites of hmDNA. Otherwise, the time for UHRF1 to recruit DNMT1 will be too long. Therefore, Bronner et al (33) proposed a new possibility that a macromolecular complex with DNMT1 formed after recruitment. The complex slides along the newly synthesized DNA for DNA replication and modification, controlled by the semi-methylation state of DNA. If hmDNA is not encountered, the SRA domain may not interact with the RFT sequencing (RFTS) domain of DNMT1, as DNMT1 has no enzymatic activity and abnormal DNA methylation will not occur. At the same time, the two combination methods can be used as a double check or double lock to ensure the fidelity of methylation map transmission. However, there is no clear and recognized binding mode, which needs to be confirmed through the interaction between the two protein structures and in vitro experiments (33).

Step 5

HAUSP removes the ubiquitin labeling from histone H3 in the synthesized intact methylated DNA region after DNA methylation modification. DNMT1 dissociates from ubiquitinated histone H3 and repeats the process when it encounters new hmDNA sites (44).

In the replication coupling stage of DNA methylation, the arginine binding cavity of the TTD domain of UHRF1 can recognize the guanidine group in the Arg121 side chain of DNA ligase 1 (LIG1), which helps the TTD domain to be recruited to the replication site through the Lys126 di/trimethylation (4547) on LIG1. Subsequently, UHRF1 monoubiquitinates Lys15 and Lys24 of the PCNA-associated factor 15 (PAF15) (48,49). PAF15 with double monoubiquitin recruits DNMT1 into the new replication chain (50). Afterwards, PAF15ub2 may be deubiquitinated by HAUSP in two cases: i) One case is the dissociation of UHRF1 from chromatin after the semi methylated DNA is converted to fully methylated DNA. The second case is the binding of DNMT1 to semi methylated DNA, which induces conformational changes in USP7 or PAF15ub2, although the mechanism is not yet fully clear (51). The two modes of methylation complement each other and work together to maintain the stable inheritance of epigenetic information.

TTD domain

TTD Domain includes two subdomains: i) TTDn and ii) TTDc. The aromatic structures constructed by F152, Y188 and Y191 in TTDn residues recognize dimethylated and trimethylated lysine residues (H3K9me2/me3). During DNA methylation, TTD and PHD domains read histone code information and transmit it to the SRA domain, allowing the SRA domain to flip methylated cytosine out of the DNA double-strand to locate the CpG site that needs to be methylated. The combination of H3K9me2/me3 and LIG1 lysine 126 dimethylation (LIG1K126me2) with UHRF1 may not play a vital role in maintaining DNA methylation (52). However, a previous study demonstrated that the arginine binding cavity in the TTD domain is crucial for the interaction of LIG1. A specific inhibitor, 5-amino-2,4-dimethylpyridine, was developed to target the Arg binding cavity. This inhibitor binds with the Arg binding cavity and effectively inhibits the binding of LIG1 and UHRF1 (53).

In addition, there is a number of studies targeting the tight binding between TTD and H3K9me2 or H3K9me3, screening and optimizing the small molecule antagonist, NV01, that disrupts this binding. This has significant reference value for studying drugs that target the structural domain (54). In addition, a recent study indicated that TTD prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3. Moreover, the H3K4me1-K9me2/3 specific binding of UHRF1-TTD to enhancers and promoters of transcription factor binding sites downregulates these genes (55).

PHD domain

As one of the most common families of chromatin reader domains, the PHD finger domain has a shallow acidic groove used to identify the N-terminal of the ligand. Recognition of the K4 methylation state of the H3N terminal tail is a relatively stable and common recognition pattern in the PHD family (5658). TTD/PHD tandem module can stimulate H3K9 methyltransferase (H3K9MT) and methylate adjacent H3K9 of adjacent nucleosomes. During this process, UHRF1-related inhibitory complexes (including DNMT1, H3K9MT, PCNA and HDAC1) may play a synergistic role (59,60), while the phosphorylation of H3 threonine 3, symmetric or asymmetric demethylation of H3R2, and acetylation of H3A1N terminal may disrupt this binding (61).

In addition, the combination of H3K9me3 with TTD-PHD also leads to a conformational change of TTD-PHD. However, this conformational change does not affect its ubiquitination activity or binding affinity with semi-methylated DNA. The potential function of this conformational change requires further studies (62). Moreover, the combination of PHD and H3 could affect the combination of TTD and H3. When the PHD domain mutates (mainly D334) or the N-terminal of H3 is modified, the PHD separates from the H3 tail, thereby disrupting or weakening the binding of TTD and methylated H3K9. Conversely, TTD mutation or histone modification (such as H3K4me3) does not affect the interaction between PHD and the unmodified H3 N-terminal (6265). This indicates that PHD is the critical domain to identify H3, which is also consistent with the aforementioned situation of TTD (66).

Previous studies have shown that the C-terminal region of Stella (also known as Dppa3/PGC7) competitively inhibits the binding of UHRF1 to H3K9me3 by binding to the PHD domain of UHRF1, thereby damaging the DNA methylation function of UHRF1. In addition, Stella can also inhibit DNA methylation by antagonizing UHRF1 activity and isolating UHRF1 from the nucleus. Disrupting Stella's interaction with UHRF1 may be a new potential direction for developing UHRF1-targeted drugs (56,67).

SRA domain
Role of SRA domain in epigenetic modification

In the process of DNA methylation modification involved in UHRF1, SRA binds to PHD, which inhibits PHD from recognizing H3R2 and keeps UHRF1 in a closed state. SRA has a high affinity and specificity for hmDNA and could be released from PHD when hmDNA exists. SRA binds to unmethylated cytosine in hmDNA through N489 in the NKR finger (483–496 residues, named after the abbreviation of asparagine, lysine and arginine) (41,68,69) and converts UHRF1 into the open state. Previously, some experiments pointed out that NKR combines with cytosine to stimulate DNA deformation and turn out cytosine instead of SRA directly (68).

P300/CBP-related factor, which is located in the NKR of the SRA domain, and HDAC1 can acetylate and deacetylate UHRF1 at K490, respectively. Acetylated UHRF1 hinders the binding of UHRF1 to hmDNA and the methylation modification of DNA, while the effect of deacetylated UHRF1 is the opposite. This indicated that abnormal DNA methylation can be eliminated by inducing the acetylation of UHRF1 in some types of cancer, thus becoming a treatment option in cancer therapy (70).

SRA can interact with HDAC1 in the methylation promoter region of some TSGs (15,71,72), including p16INK4a and p14ARF (also known as mouse p19ARF). In addition, studies have shown that SRA can also impact the expression of TSGs by altering their acetylation. For example, the SRA domain interacts with the histone acetyltransferase domain of KAT7, partially inhibiting the acetylation of H3K14 on the TUSC3 gene promoter mediated by KAT7, thereby inhibiting the expression of TUSC3 and affecting the proliferation of colon cancer cells (73). A recent study demonstrated that the SRA domain may also affect ubiquitination modification. The SRA domain of UHRF1 binds with the AF2 domain of estrogen receptors α (ERα), thereby suppressing K48 ubiquitination in ERα and enhancing its stability. This provides a new idea for the treatment of breast cancer (74). SRA has varying effects on different genes in different cancers, therefore further research on SRA is needed for targeted cancer treatment.

Role of SRA as a cancer-targeting drug

SRA domain is the unique domain of UHRF1 and UHRF2 (32). Therefore, a compound targeting the SRA domain will be a specific inhibitor for UHFR1, such as chicoric acid (75), uracil derivative NSC232003 (71) and epigallocatechin-3-gallate (EGCG). EGCG can downregulate UHRF1 and DNMT1, reverse the methylation of tumor suppressor p16INK4a and induce cell cycle arrest and apoptosis in Jurkat cells (24). The anthraquinone compound UM63 (an inhibitor of this process) performs the role of 5mC in DNA methylation. UM63 can merge with a 5mC binding pocket to inhibit the base reversal process and reduce the overall DNA methylation by damaging the UHRF1/DNMT1 interaction (76).

Based on the UM63 structure, some studies have identified new inhibitors of UHRF1-SRA, such as AMSA2 and MPB7, using multidisciplinary methods. Similar to UM63, they can inhibit SRA-mediated base flipping at low concentrations but do not intercalate into DNA. These inhibitors prevent the involvement of UHRF1 and DNMT1 in DNA methylation. In addition, because they prioritize affecting cells with high levels of UHRF1, they will reduce damage to normal cells (77). Another inhibitor targeting the SRA domain, UF146, has been shown to effectively eradicate leukemia-initiating cells, confirming the potential of UHRF1 inhibitors in cancer treatment (78). However, due to UF146 being a pan-assay interference compound (79), its specificity is not high, and it may have unpredictable reactions with numerous biological targets, resulting in false positive results (80). Through molecular docking, molecular dynamics simulation and toxicity analysis, other inhibitors targeting the SRA domain can also be screened, such as chicoric acid. However, the specific therapeutic effects and indications require extensive experiments for further verification and screening (75).

UBL domain

UBL domain is also known as the N-terminal of a novel Np95/icbp90-like ring finger protein, which is the target of single- and multi-ubiquitination (81). Some studies have proved that UHRF1 cannot play its role in DNA methylation modification without the UBL domain (47,82,83). This highlights the two crucial functions of UBL in DNA methylation inheritance (47): i) Cooperating with the RING domain to ubiquitinate histone H3, recruiting the ubiquitin-binding enzyme E2 to form a stable E2/ubiquitin ligase E3 /chromatin complex. Subsequently, ubiquitin is transferred from E2 to histone H3 (this binding is universal, meaning that other proteins containing the UBL domain can also occur); ii) UBL recruits DNMT1 into chromatin through a hydrophobic patch and enhances DNMT activity by binding to DNMT1-621 (amino acids: 621–1,616) (47,82,83).

RING domain

RING Domain has ubiquitin ligase activity, including ubiquitination of UHRF1 itself. UHRF1 protects itself from ubiquitination by interacting with HAUSP (69). The natural compound thymoquinone (TQ) eliminates the protective effect on UHRF1 by reducing the expression of HAUSP, leading to the ubiquitination of UHRF1 under the action of ubiquitin ligase, reactivating TSG, inhibiting cell proliferation, promoting cell cycle arrest and inducing apoptosis (84). TQ can selectively induce the degradation of UHRF1 in cancer cells without affecting its expression level in normal cells (85). In addition to TQ, a recent study has observed that diosgenin (DSG) induces the dissociation of UHRF1 and HAUSP protein complexes by directly binding to UHRF1, inhibiting the protective effect of HAUSP to UHRF1, thereby reducing the expression of UHRF1 and increasing the expression of TSGs. However, the specific binding sites between DSG and UHRF1 are not clear, and the effect of DSG needs to be achieved at high drug concentrations (86). Therefore, further research is needed.

As a ubiquitin ligase, RING ubiquitinates the target genes of DNMT1, which are histone H3Lys23 and Lys18 (87,88). The ubiquitin ligase activity of the RING domain is crucial for the growth of tumor cells, and inhibitors targeting this activity may be a method to produce anticancer drugs (16). In addition to tumor cells, a previous study indicated that the RING domain can interact with the human immunodeficiency virus type 1 (HIV-1) protein Tat, which is involved in virus replication, thus promoting the ubiquitination degradation of Tat, inhibiting HIV-1 transcription and maintaining HIV-1 latency (89).

Linker domain

In the methylation modification involving UHRF1, the linker replaces the H3 tail in the TTD peptide binding tank so that the H3 tail connects PHD at the N-terminal and the TTD domain at K9me3. The two arginine and one lysine of the linker residue (R295-R296-K297) are essential to stabilize this TTD-PHD conformation (64,65). Additionally, phosphorylation of S298 in linker can change the interaction between UHRF1 and H3, potentially serving as a functional switch for UHRF1 and participating in a variety of regulatory pathways, including DNA methylation maintenance, transcriptional inhibition and cell cycle progression (17). In vitro studies have confirmed that PIM1, an essential regulatory factor of aging, can regulate the function of UHRF1 through Ser311 phosphorylation. This regulation inhibits the binding of TTD-PHD to H3K9me3, thereby affecting the activation of DNMT1 and triggering DNA hypomethylation (90).

PBR domain

PBR Domain has five kinds of functions: i) It binds to TTD in the closed state of UHRF1, inhibiting its interaction with H3K9me3; ii) it promotes the recognition and binding of SRA and hmDNA; iii) it enhances the interaction between RFTS of DNMT1 and SRA (36); iv) it interacts with the UBL1 and UBL2 domains of HAUSP, keeping UHRF1 in the open state and facilitating the binding of UHRF1 to H3K9me3 (65,91,92); and v) it binds to PI5P, opening the closed conformation of UHRF1 and increasing the affinity of H3K9me3 for TTD (38). All domains of UHRF2 and UHRF1 have a very high sequence similarity, except for pRb (93). This may be why UHRF2 cannot replace UHRF1 to maintain DNA methylation (94).


Targeting the highly expressed oncoproteins or genes is a novel approach to anticancer drugs research (66). As a multifunctional epigenetic modifier, UHRF1 has significant differential expression between tumor and normal tissues and is a potential cancer treatment target. Overexpression of UHRF1 can silence TSGs, inhibit DNA repair and apoptosis and promote tumor growth and migration. Conversely, the deletion of UHRF1 leads to DNA demethylation and histone acetylation, which promotes tumor cell apoptosis and inhibits tumor proliferation and invasion through TSGs reactivation and DNA repair (44).

Moreover, the expression of UHRF1 was an independent factor affecting overall survival (OS) and progression-free survival (PFS) (OS, P=0.038; PFS, P=0.014) (95). A previous study reported that patients with elevated UHRF1 levels had lower OS and PFS (96). The high expression of UHRF1 may also be related to tumor size, stage and metastasis (97). It has been reported that UHRF1 can be used as a cancer diagnostic tool, stem cell marker and therapeutic tool (98). With the progress of research on the function and mechanism of UHRF1 in cancer, the clinical research on UHRF1 will be more extensive and profound.

There are three directions of targeted drugs for UHRF1. One direction aims for the complex composed of UHRF1, such as DNMT1, HDAC1 and HAUSP in ECReM. For example, combining UHRF1 and low-dose DNMT inhibitors can effectively reduce DNA methylation and reactivate TSGs (99). Due to the expression level of UHRF1 in all normal tissues being 5–70-fold lower than that of HDAC1 and DNMT1, the side effects of UHRF1 inhibitors are moderate compared with current HDAC and DNMT inhibitors. This can help reduce the tolerance of the patients to DNMT inhibitors. In addition, a previous study revealed that loss of UHRF1, combined with HDAC inhibition, can reactivate TSGs and inhibit the proliferation of colorectal cancer cells (100). The second direction is targeted at UHRF1 domains. Since UHRF1 has multiple functional domains, it is necessary to clarify the function of each domain to determine which of the several domains can achieve sufficient tumor inhibition effect (66). At present, the regulation mechanism of UHRF1 has been detected in a variety of cancers (40), which plays an enlightening role in clinical treatment, especially in personalized therapies. The last method is to indirectly inhibit the expression of UHRF1 by affecting the upstream molecules. For example, in prostate cancer, especially in cases that are resistant to abiraterone, UHRF1 and p-AKT are abnormally overexpressed. AKT phosphorylation inhibitor MK2206 can induce the degradation of UHRF1 protein, thereby increasing the expression of epigenetic silenced TSGs (such as p21), and reducing the typical biomarkers of neuroendocrine prostate cancer in prostate neuroendocrine carcinoma, SYP and NCAM1, thereby improving the therapeutic effect of abiraterone on tumors (101). The present review aimed to provide ideas for drug research and direction for the functional identification of other proteins with similar structures by clarifying the function and regulatory pathway of UHRF1 domains.


Not applicable.


The present study was supported by the National Natural Science Foundation of China (grant no. 81802761) and Natural Science Foundation of Shandong Province (grant no. ZR2023MH258).

Availability of data and materials

Not applicable.

Authors' contributions

YZ conceptualized the study and approved the final version of the manuscript. YS made substantial contributions in writing the original draft. HL responded to the questions raised by the reviewers, made systematic revisions to the article, and gave the final approval of the version to be published. QX, CG and MX were mainly involved in the interpretation of the data through the figures. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.







ubiquitin like with PHD and ring finger domains 1


tumor suppressor genes


N-terminal ubiquitin-like domain


tandem Tudor domain


plant homeodomain


set and ring-associated domain


really interesting new gene domain


herpes virus-associated ubiquitin-specific protease


histone deacetylase 1


estrogen receptors α


proliferating cell nuclear antigen


retinoblastoma gene product


epigenetic code replication machinery




hemi-methylated DNA




the replication foci targeting




ubiquitin-binding enzyme






human immunodeficiency virus type 1


overall survival


progression-free survival



Probst AV, Dunleavy E and Almouzni G: Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol. 10:192–206. 2009. View Article : Google Scholar : PubMed/NCBI


Zafon C, Gil J, Pérez-González B and Jordà M: DNA methylation in thyroid cancer. Endocr Relat Cancer. 26:R415–R439. 2019. View Article : Google Scholar : PubMed/NCBI


Abhishek S, Nakarakanti NK, Deeksha W and Rajakumara E: Mechanistic insights into recognition of symmetric methylated cytosines in CpG and non-CpG DNA by UHRF1 SRA. Int J Biol Macromol. 170:514–522. 2021. View Article : Google Scholar : PubMed/NCBI


Bronner C, Krifa M and Mousli M: Increasing role of UHRF1 in the reading and inheritance of the epigenetic code as well as in tumorogenesis. Biochem Pharmacol. 86:1643–1649. 2013. View Article : Google Scholar : PubMed/NCBI


Sheng Y, Wang H, Liu D and Zhang C, Deng Y, Yang F, Zhang T and Zhang C: Methylation of tumor suppressor gene CDH13 and SHP1 promoters and their epigenetic regulation by the UHRF1/PRMT5 complex in endometrial carcinoma. Gynecol Oncol. 140:145–151. 2016. View Article : Google Scholar : PubMed/NCBI


Daskalos A, Oleksiewicz U, Filia A, Nikolaidis G, Xinarianos G, Gosney JR, Malliri A, Field JK and Liloglou T: UHRF1-mediated tumor suppressor gene inactivation in nonsmall cell lung cancer. Cancer. 117:1027–1037. 2011. View Article : Google Scholar : PubMed/NCBI


Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI, Chen X, Kojima K, Thung S, Bronson RT, et al: UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell. 25:196–209. 2014. View Article : Google Scholar : PubMed/NCBI


Zhuo H, Tang J, Lin Z, Jiang R, Zhang X, Ji J, Wang P and Sun B: The aberrant expression of MEG3 regulated by UHRF1 predicts the prognosis of hepatocellular carcinoma. Mol Carcinog. 55:209–219. 2016. View Article : Google Scholar : PubMed/NCBI


Reardon ES, Shukla V, Xi S, Gara SK, Liu Y, Straughan D, Zhang M, Hong JA, Payabyab EC, Kumari A, et al: UHRF1 is a novel druggable epigenetic target in malignant pleural mesothelioma. J Thorac Oncol. 16:89–103. 2021. View Article : Google Scholar : PubMed/NCBI


Nakamura K, Baba Y, Kosumi K, Harada K, Shigaki H, Miyake K, Kiyozumi Y, Ohuchi M, Kurashige J, Ishimoto T, et al: UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma. Oncotarget. 7:57821–57831. 2016. View Article : Google Scholar : PubMed/NCBI


Hervouet E, Lalier L, Debien E, Cheray M, Geairon A, Rogniaux H, Loussouarn D, Martin SA, Vallette FM and Cartron PF: Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells. PLoS One. 5:e113332010. View Article : Google Scholar : PubMed/NCBI


Kan G, He H, Zhao Q, Li X, Li M, Yang H and Kim JK: Functional dissection of the role of UHRF1 in the regulation of retinoblastoma methylome. Oncotarget. 8:39497–39511. 2017. View Article : Google Scholar : PubMed/NCBI


Obata Y, Furusawa Y, Endo TA, Sharif J, Takahashi D, Atarashi K, Nakayama M, Onawa S, Fujimura Y, Takahashi M, et al: The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells. Nat Immunol. 15:571–579. 2014. View Article : Google Scholar : PubMed/NCBI


Elia L, Kunderfranco P, Carullo P, Vacchiano M, Farina FM, Hall IF, Mantero S, Panico C, Papait R, Condorelli G and Quintavalle M: UHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial disease. J Clin Invest. 128:2473–2486. 2018. View Article : Google Scholar : PubMed/NCBI


Unoki M, Nishidate T and Nakamura Y: ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene. 23:7601–7610. 2004. View Article : Google Scholar : PubMed/NCBI


Jenkins Y, Markovtsov V, Lang W, Sharma P, Pearsall D, Warner J, Franci C, Huang B, Huang J, Yam GC, et al: Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth. Mol Biol Cell. 16:5621–569. 2005. View Article : Google Scholar : PubMed/NCBI


Unoki M, Brunet J and Mousli M: Drug discovery targeting epigenetic codes: The great potential of UHRF1, which links DNA methylation and histone modifications, as a drug target in cancers and toxoplasmosis. Biochem Pharmacol. 78:1279–1288. 2009. View Article : Google Scholar : PubMed/NCBI


Mousli M, Hopfner R, Abbady AQ, Monté D, Jeanblanc M, Oudet P, Louis B and Bronner C: ICBP90 belongs to a new family of proteins with an expression that is deregulated in cancer cells. Br J Cancer. 89:120–127. 2003. View Article : Google Scholar : PubMed/NCBI


Unoki M, Kelly JD, Neal DE, Ponder BA, Nakamura Y and Hamamoto R: UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer. Br J Cancer. 101:98–105. 2009. View Article : Google Scholar : PubMed/NCBI


Crnogorac-Jurcevic T, Gangeswaran R, Bhakta V, Capurso G, Lattimore S, Akada M, Sunamura M, Prime W, Campbell F, Brentnall TA, et al: Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma. Gastroenterology. 129:1454–1463. 2005. View Article : Google Scholar : PubMed/NCBI


Lorenzato M, Caudroy S, Bronner C, Evrard G, Simon M, Durlach A, Birembaut P and Clavel C: Cell cycle and/or proliferation markers: What is the best method to discriminate cervical high-grade lesions? Hum Pathol. 36:1101–1107. 2005. View Article : Google Scholar : PubMed/NCBI


Liu Y, Cheng D, Wang Y, Xi S, Wang T, Sun W, Li G, Ma D, Zhou S, Li Z and Ni C: UHRF1-mediated ferroptosis promotes pulmonary fibrosis via epigenetic repression of GPX4 and FSP1 genes. Cell Death Dis. 13:10702022. View Article : Google Scholar : PubMed/NCBI


Fang L, Hao Y, Yu H, Gu X, Peng Q, Zhuo H, Li Y, Liu Z, Wang J, Chen Y, et al: Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity. Cancer Cell. 41:1118–1133. 2023. View Article : Google Scholar : PubMed/NCBI


Achour M, Mousli M, Alhosin M, Ibrahim A, Peluso J, Muller CD, Schini-Kerth VB, Hamiche A, Dhe-Paganon S and Bronner C: Epigallocatechin-3-gallate up-regulates tumor suppressor gene expression via a reactive oxygen species-dependent down-regulation of UHRF1. Biochem Biophys Res Commun. 430:208–212. 2013. View Article : Google Scholar : PubMed/NCBI


Alhosin M, Abusnina A, Achour M, Sharif T, Muller C, Peluso J, Chataigneau T, Lugnier C, Schini-Kerth VB, Bronner C and Fuhrmann G: Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1. Biochem Pharmacol. 79:1251–1260. 2010. View Article : Google Scholar : PubMed/NCBI


Alhosin M, Sharif T, Mousli M, Etienne-Selloum N, Fuhrmann G, Schini-Kerth VB and Bronner C: Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties. J Exp Clin Cancer Res. 30:412011. View Article : Google Scholar : PubMed/NCBI


Krifa M, Alhosin M, Muller CD, Gies JP, Chekir-Ghedira L, Ghedira K, Mély Y, Bronner C and Mousli M: Limoniastrum guyonianum aqueous gall extract induces apoptosis in human cervical cancer cells involving p16 INK4A re-expression related to UHRF1 and DNMT1 down-regulation. J Exp Clin Cancer Res. 32:302013. View Article : Google Scholar : PubMed/NCBI


Abusnina A, Alhosin M, Keravis T, Muller CD, Fuhrmann G, Bronner C and Lugnier C: Down-regulation of cyclic nucleotide phosphodiesterase PDE1A is the key event of p73 and UHRF1 deregulation in thymoquinone-induced acute lymphoblastic leukemia cell apoptosis. Cell Signal. 23:152–160. 2011. View Article : Google Scholar : PubMed/NCBI


Yang C, Wang Y, Zhang F, Sun G, Li C, Jing S, Liu Q and Cheng Y: Inhibiting UHRF1 expression enhances radiosensitivity in human esophageal squamous cell carcinoma. Mol Biol Rep. 40:5225–5235. 2013. View Article : Google Scholar : PubMed/NCBI


Gao L, Tan XF, Zhang S, Wu T, Zhang ZM, Ai HW and Song J: An intramolecular interaction of uhrf1 reveals dual control for its histone association. Structure. 26:304–311. 2018. View Article : Google Scholar : PubMed/NCBI


Kong X, Chen J, Xie W, Brown SM, Cai Y, Wu K, Fan D, Nie Y, Yegnasubramanian S, Tiedemann RL, et al: Defining UHRF1 domains that support maintenance of human colon cancer DNA methylation and oncogenic properties. Cancer Cell. 35:633–648. 2019. View Article : Google Scholar : PubMed/NCBI


Bronner C, Achour M, Arima Y, Chataigneau T, Saya H and Schini-Kerth VB: The UHRF family: Oncogenes that are drugable targets for cancer therapy in the near future? Pharmacol Therap. 115:419–434. 2007. View Article : Google Scholar : PubMed/NCBI


Bronner C, Alhosin M, Hamiche A and Mousli M: Coordinated dialogue between UHRF1 and DNMT1 to ensure faithful inheritance of methylated DNA patterns. Genes (Basel). 10:652019. View Article : Google Scholar : PubMed/NCBI


Schultz MD, He Y, Whitaker JW, Hariharan M, Mukamel EA, Leung D, Rajagopal N, Nery JR, Urich MA, Chen H, et al: Human body epigenome maps reveal noncanonical DNA methylation variation. Nature. 523:212–216. 2015. View Article : Google Scholar : PubMed/NCBI


Ming X, Zhang Z, Zou Z, Lv C, Dong Q, He Q, Yi Y, Li Y, Wang H and Zhu B: Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration. Cell Res. 30:980–996. 2020. View Article : Google Scholar : PubMed/NCBI


Harrison JS, Cornett EM, Goldfarb D, DaRosa PA, Li ZM, Yan F, Dickson BM, Guo AH, Cantu DV, Kaustov L, et al: Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. ELife. 5:e171012016. View Article : Google Scholar : PubMed/NCBI


Xue B, Zhao J, Feng P, Xing J, Wu H and Li Y: Epigenetic mechanism and target therapy of UHRF1 protein complex in malignancies. Onco Targets Ther. 12:549–559. 2019. View Article : Google Scholar : PubMed/NCBI


Gelato KA, Tauber M, Ong MS, Winter S, Hiragami-Hamada K, Sindlinger J, Lemak A, Bultsma Y, Houliston S, Schwarzer D, et al: Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate. Mol Cell. 54:905–919. 2014. View Article : Google Scholar : PubMed/NCBI


Greiner VJ, Kovalenko L, Humbert N, Richert L, Birck C, Ruff M, Zaporozhets OA, Dhe-Paganon S, Bronner C and Mély Y: Site-selective monitoring of the interaction of the SRA domain of UHRF1 with target DNA sequences labeled with 2-aminopurine. Biochemistry. 54:6012–6020. 2015. View Article : Google Scholar : PubMed/NCBI


Hashimoto H, Horton JR, Zhang X, Bostick M, Jacobsen SE and Cheng X: The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature. 455:826–829. 2008. View Article : Google Scholar : PubMed/NCBI


Avvakumov GV, Walker JR, Xue S, Li Y, Duan S, Bronner C, Arrowsmith CH and Dhe-Paganon S: Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature. 455:822–825. 2008. View Article : Google Scholar : PubMed/NCBI


Arita K, Ariyoshi M, Tochio H, Nakamura Y and Shirakawa M: Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature. 455:818–821. 2008. View Article : Google Scholar : PubMed/NCBI


Zhang H, Liu Y, Xie Y, Zhu Y, Liu J and Lu F: H3K27me3 shapes DNA methylome by inhibiting UHRF1-mediated H3 ubiquitination. Sci China Life Sci. 65:1685–1700. 2022. View Article : Google Scholar : PubMed/NCBI


Xie S and Qian C: The growing complexity of UHRF1-mediated maintenance DNA methylation. Genes (Basel). 9:6002018. View Article : Google Scholar : PubMed/NCBI


Ferry L, Fournier A, Tsusaka T, Adelmant G, Shimazu T, Matano S, Kirsh O, Amouroux R, Dohmae N, Suzuki T, et al: Methylation of DNA ligase 1 by G9a/GLP recruits UHRF1 to replicating DNA and regulates DNA methylation. Mol Cell. 67:550–565. 2017. View Article : Google Scholar : PubMed/NCBI


Kori S, Ferry L, Matano S, Jimenji T, Kodera N, Tsusaka T, Matsumura R, Oda T, Sato M, Dohmae N, et al: Structure of the UHRF1 tandem tudor domain bound to a methylated non-histone protein, LIG1, reveals rules for binding and regulation. Structure. 27:485–496. 2019. View Article : Google Scholar : PubMed/NCBI


Li T, Wang L, Du Y, Xie S, Yang X, Lian F, Zhou Z and Qian C: Structural and mechanistic insights into UHRF1-mediated DNMT1 activation in the maintenance DNA methylation. Nucl Acids Res. 46:3218–3231. 2018. View Article : Google Scholar : PubMed/NCBI


Povlsen LK, Beli P, Wagner SA, Poulsen SL, Sylvestersen KB, Poulsen JW, Nielsen ML, Bekker-Jensen S, Mailand N and Choudhary C: Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass. Nat Cell Biol. 14:1089–1098. 2012. View Article : Google Scholar : PubMed/NCBI


Karg E, Smets M, Ryan J, Forné I, Qin W, Mulholland CB, Kalideris G, Imhof A, Bultmann S and Leonhardt H: Ubiquitome analysis reveals PCNA-associated factor 15 (PAF15) as a specific ubiquitination target of UHRF1 in embryonic stem cells. J Mol Biol. 429:3814–3824. 2017. View Article : Google Scholar : PubMed/NCBI


González-Magaña A, de Opakua AI, Merino N, Monteiro H, Diercks T, Murciano-Calles J, Luque I, Bernadó P, Cordeiro TN, Biasio A and Blanco FJ: Double monoubiquitination modifies the molecular recognition properties of p15(PAF) promoting binding to the reader module of Dnmt1. ACS Chem Biol. 14:2315–2326. 2019.PubMed/NCBI


Miyashita R, Nishiyama A, Qin W, Chiba Y, Kori S, Kato N, Konishi C, Kumamoto S, Kozuka-Hata H, Oyama M, et al: The termination of UHRF1-dependent PAF15 ubiquitin signaling is regulated by USP7 and ATAD5. Elife. 12:e790132023. View Article : Google Scholar : PubMed/NCBI


Bronner C, Krifa M and Mousli M: Increasing role of UHRF1 in the reading and inheritance of the epigenetic code as well as in tumorogenesis. Biochem Pharmacol. 86:1643–1649. 2013. View Article : Google Scholar : PubMed/NCBI


Kori S, Shibahashi Y, Ekimoto T, Nishiyama A, Yoshimi S, Yamaguchi K, Nagatoishi S, Ohta M, Tsumoto K, Nakanishi M, et al: Structure-based screening combined with computational and biochemical analyses identified the inhibitor targeting the binding of DNA Ligase 1 to UHRF1. Bioorg Med Chem. 52:1165002021. View Article : Google Scholar : PubMed/NCBI


Senisterra G, Zhu HY, Luo X, Zhang H, Xun G, Lu C, Xiaon W, Hajian T, Loppnau P, Chau I, et al: Discovery of small-molecule antagonists of the H3K9me3 binding to UHRF1 tandem tudor domain. SLAS Discov. 23:930–940. 2018. View Article : Google Scholar : PubMed/NCBI


Choudalakis M, Kungulovski G, Mauser R, Bashtrykov P and Jeltsch A: Refined read-out: The hUHRF1 Tandem-Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3. Protein Sci. 32:e47602023. View Article : Google Scholar : PubMed/NCBI


Hata K, Kobayashi N, Sugimura K, Qin W, Haxholli D, Chiba Y, Yoshimi S, Hayashi G, Onoda H, Ikegami T, et al: Structural basis for the unique multifaceted interaction of DPPA3 with the UHRF1 PHD finger. Nucleic Acids Res. 50:12527–12542. 2022. View Article : Google Scholar : PubMed/NCBI


Jain K, Fraser CS, Marunde MR, Parker MM, Sagum C, Burg JM, Hall N, Popova IK, Rodriguez KL, Vaidya A, et al: Characterization of the plant homeodomain (PHD) reader family for their histone tail interactions. Epigenetics Chromatin. 13:32020. View Article : Google Scholar : PubMed/NCBI


Musselman CA and Kutateladze TG: Handpicking epigenetic marks with PHD fingers. Nucleic Acids Res. 39:9061–9071. 2011. View Article : Google Scholar : PubMed/NCBI


Xie S, Jakoncic J and Qian C: UHRF1 double tudor domain and the adjacent PHD finger act together to recognize K9me3-containing histone H3 tail. J Mol Biol. 415:318–328. 2012. View Article : Google Scholar : PubMed/NCBI


Morinière J, Rousseaux S, Steuerwald U, Soler-López M, Curtet S, Vitte AL, Govin J, Gaucher J, Sadoul K, Hart DJ, et al: Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature. 461:664–668. 2009. View Article : Google Scholar : PubMed/NCBI


Rajakumara E, Wang Z, Ma H, Hu L, Chen H, Lin Y, Guo R, Wu F, Li H, Lan F, et al: PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression. Mol Cell. 43:275–284. 2011. View Article : Google Scholar : PubMed/NCBI


Cheng J, Yang Y, Fang J, Xiao J, Zhu T, Chen F, Wang P, Li Z, Yang H and Xu Y: Structural insight into coordinated recognition of trimethylated histone H3 lysine 9 (H3K9me3) by the plant homeodomain (PHD) and tandem tudor domain (TTD) of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) protein. J Biol Chem. 288:1329–1339. 2013. View Article : Google Scholar : PubMed/NCBI


Rothbart SB, Krajewski K, Nady N, Tempel W, Xue S, Badeaux AI, Barsyte-Lovejoy D, Martinez JY, Bedford MT, Fuchs SM, et al: Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. Nat Struct Mol Biol. 19:1155–1160. 2012. View Article : Google Scholar : PubMed/NCBI


Arita K, Isogai S, Oda T, Unoki M, Sugita K, Sekiyama N, Kuwata K, Hamamoto R, Tochio H, Sato M, et al: Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. Proc Natl Acad Sci USA. 109:12950–1295. 2012. View Article : Google Scholar : PubMed/NCBI


Rothbart SB, Dickson BM, Ong MS, Krajewski K, Houliston S, Kireev DB, Arrowsmith CH and Strahl BD: Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation. Genes Dev. 27:1288–1298. 2013. View Article : Google Scholar : PubMed/NCBI


Unoki M: Current and potential anticancer drugs targeting members of the UHRF1 complex including epigenetic modifiers. Recent Pat Anticancer Drug Discov. 6:116–130. 2011. View Article : Google Scholar : PubMed/NCBI


Du W, Dong Q, Zhang Z, Liu B, Zhou T, Xu RM, Wang H, Zhu B and Li Y: Stella protein facilitates DNA demethylation by disrupting the chromatin association of the RING finger-type E3 ubiquitin ligase UHRF1. J Biol Chem. 294:8907–8917. 2019. View Article : Google Scholar : PubMed/NCBI


Vaughan RM, Rothbart SB and Dickson BM: The finger loop of the SRA domain in the E3 ligase UHRF1 is a regulator of ubiquitin targeting and is required for the maintenance of DNA methylation. J Biol Chem. 294:15724–15732. 2019. View Article : Google Scholar : PubMed/NCBI


Alhosin M, Omran Z, Zamzami MA, Al-Malki AL, Choudhry H, Mousli M and Bronner C: Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer. J Exp Clin Cancer Res. 35:1742016. View Article : Google Scholar : PubMed/NCBI


Hahm JY, Park JW, Kang JY, Park J, Kim CH, Kim JY, Ha NC, Kim JW and Seo SB: Acetylation of UHRF1 regulates hemi--methylated DNA binding and maintenance of Genome-wide DNA methylation. Cell Rep. 32:1079582020. View Article : Google Scholar : PubMed/NCBI


Achour M, Jacq X, Rondé P, Alhosin M, Charlot C, Chataigneau T, Jeanblanc M, Macaluso M, Giordano A, Hughes AD, et al: The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene. 27:2187–2197. 2008. View Article : Google Scholar : PubMed/NCBI


Bashtrykov P, Jankevicius G, Jurkowska RZ, Ragozin S and Jeltsch A: The UHRF1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase DNMT1 by an allosteric mechanism. J Biol Chem. 289:4106–4115. 2014. View Article : Google Scholar : PubMed/NCBI


Taniue K, Hayashi T, Kamoshida Y, Kurimoto A, Takeda Y, Negishi L, Iwasaki K, Kawamura Y, Goshima N and Akiyama T: UHRF1-KAT7-mediated regulation of TUSC3 expression via histone methylation/acetylation is critical for the proliferation of colon cancer cells. Oncogene. 39:1018–1030. 2020. View Article : Google Scholar : PubMed/NCBI


Luo G, Li Q, Yu M, Wang T, Zang Y, Liu Z, Niu Z, Yang H and Lai J: UHRF1 modulates breast cancer cell growth via estrogen signaling. Med Oncol. 39:1112022. View Article : Google Scholar : PubMed/NCBI


Awal MA, Nur SM, Al Khalaf AK, Rehan M, Ahmad A, Hosawi SBI, Choudhry H and Khan MI: Structural-guided identification of small molecule inhibitor of UHRF1 methyltransferase activity. Front Gene. 13:9288842022. View Article : Google Scholar : PubMed/NCBI


Zaayter L, Mori M, Ahmad T, Ashraf W, Boudier C, Kilin V, Gavvala K, Richert L, Eiler S, Ruff M, et al: A molecular tool targeting the base-flipping activity of human UHRF1. Chemistry. 25:13363–13375. 2019. View Article : Google Scholar : PubMed/NCBI


Ciaco S, Mazzoleni V, Javed A, Eiler S, Ruff M, Mousli M, Mori M and Mély Y: Inhibitors of UHRF1 base flipping activity showing cytotoxicity against cancer cells. Bioorg Chem. 137:1066162023. View Article : Google Scholar : PubMed/NCBI


Hu CL, Chen BY, Li Z, Yang T, Xu CH, Yang R, Yu PC, Zhao J, Liu T, Liu N, et al: Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia. Cell Res. 32:1105–1123. 2022. View Article : Google Scholar : PubMed/NCBI


Baell JB and Holloway GA: New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem. 53:2719–2740. 2010. View Article : Google Scholar : PubMed/NCBI


Baell J and Walters MA: Chemistry: Chemical con artists foil drug discovery. Nature. 513:481–483. 2014. View Article : Google Scholar : PubMed/NCBI


Nady N, Lemak A, Walker JR, Avvakumov GV, Kareta MS, Achour M, Xue S, Duan S, Allali-Hassani A, Zuo X, et al: Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. J Biol Chem. 286:24300–24311. 2011. View Article : Google Scholar : PubMed/NCBI


DaRosa PA, Harrison JS, Zelter A, Davis TN, Brzovic P, Kuhlman B and Klevit RE: A bifunctional role for the UHRF1 UBL domain in the control of hemi-methylated DNA-dependent histone ubiquitylation. Mol Cell. 72:753–765. 2018. View Article : Google Scholar : PubMed/NCBI


Foster BM, Stolz P, Mulholland CB, Montoya A, Kramer H, Bultmann S and Bartke T: Critical role of the UBL domain in stimulating the E3 ubiquitin ligase activity of UHRF1 toward chromatin. Mol Cell. 72:739–752. 2018. View Article : Google Scholar : PubMed/NCBI


Abdullah O, Omran Z, Hosawi S, Hamiche A, Bronner C and Alhosin M: Thymoquinone is a multitarget single epidrug that inhibits the UHRF1 protein complex. Genes (Basel). 12:6222021. View Article : Google Scholar : PubMed/NCBI


Alhosin M, Ibrahim A, Boukhari A, Sharif T, Gies JP, Auger C and Schini-Kerth VB: Anti-neoplastic agent thymoquinone induces degradation of α and β tubulin proteins in human cancer cells without affecting their level in normal human fibroblasts. Invest New Drugs. 30:1813–1819. 2012. View Article : Google Scholar : PubMed/NCBI


Peng Y, Tang R, Ding L, Zheng R, Liu Y, Yin L, Fu Y, Deng T and Li X: Diosgenin inhibits prostate cancer progression by inducing UHRF1 protein degradation. Eur J Pharmacol. 942:1755222023. View Article : Google Scholar : PubMed/NCBI


Nishiyama A, Yamaguchi L, Sharif J, Johmura Y, Kawamura T, Nakanishi K, Shimamura S, Arita K, Kodama T, Ishikawa F, et al: Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature. 502:249–253. 2013. View Article : Google Scholar : PubMed/NCBI


Qin W, Wolf P, Liu N, Link S, Smets M, La Mastra F, Forné I, Pichler G, Hörl D, Fellinger K, et al: DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Res. 25:911–929. 2015. View Article : Google Scholar : PubMed/NCBI


Liang T, Zhang Q, Wu Z, Chen P, Huang Y, Liu S and Li L: UHRF1 suppresses HIV-1 transcription and promotes HIV-1 latency by competing with p-TEFb for ubiquitination-proteasomal degradation of tat. mBio. 12:e01625212021. View Article : Google Scholar : PubMed/NCBI


Yang J, Liu K, Yang J, Jin B, Chen H, Zhan X, Li Z, Wang L, Shen X, Li M, et al: PIM1 induces cellular senescence through phosphorylation of UHRF1 at Ser311. Oncogene. 36:4828–4842. 2017. View Article : Google Scholar : PubMed/NCBI


Chu J, Loughlin EA, Gaur NA, SenBanerjee S, Jacob V, Monson C, Kent B, Oranu A, Ding Y, Ukomadu C and Sadler KC: UHRF1 phosphorylation by cyclin A2/cyclin-dependent kinase 2 is required for zebrafish embryogenesis. Mol Biol Cell. 23:59–70. 2012. View Article : Google Scholar : PubMed/NCBI


Zhang ZM, Rothbart SB, Allison DF, Cai Q, Harrison JS, Li L, Wang Y, Strahl BD, Wang GG and Song J: An allosteric interaction links USP7 to deubiquitination and chromatin targeting of UHRF1. Cell Rep. 12:1400–1406. 2015. View Article : Google Scholar : PubMed/NCBI


Fang J, Cheng J, Wang J, Zhang Q, Liu M, Gong R, Wang P, Zhang X, Feng Y, Lan W, et al: Hemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition. Nat Commun. 7:111972016. View Article : Google Scholar : PubMed/NCBI


Zhang J, Gao Q, Li P, Liu X, Jia Y, Wu W, Li J, Dong S, Koseki H and Wong J: S phase-dependent interaction with DNMT1 dictates the role of UHRF1 but not UHRF2 in DNA methylation maintenance. Cell Res. 21:1723–1739. 2011. View Article : Google Scholar : PubMed/NCBI


Geng Y, Gao Y, Ju H and Yan F: Diagnostic and prognostic value of plasma and tissue ubiquitin-like, containing PHD and RING finger domains 1 in breast cancer patients. Cancer Sci. 104:194–199. 2013. View Article : Google Scholar : PubMed/NCBI


Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, Lai KM, Ji J, Dudoit S, Ng IO, et al: Gene expression patterns in human liver cancers. Mol Biol Cell. 13:1929–1939. 2002. View Article : Google Scholar : PubMed/NCBI


Zhu M, Xu Y, Ge M, Gui Z and Yan F: Regulation of UHRF1 by microRNA-9 modulates colorectal cancer cell proliferation and apoptosis. Cancer Sci. 106:833–839. 2015. View Article : Google Scholar : PubMed/NCBI


Yang H, Cheung S and Churg A: UHRF1 Immunohistochemical staining separates benign reactive spindle cell mesothelial proliferations from sarcomatoid mesotheliomas. Am J Surg Pathol. 46:840–845. 2022. View Article : Google Scholar : PubMed/NCBI


Cai Y, Tsai HC, Yen RC, Zhang YW, Kong X, Wang W, Xia L and Baylin SB: Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells. Genome Res. 27:533–544. 2017. View Article : Google Scholar : PubMed/NCBI


Niinuma T, Kitajima H, Kai M, Yamamoto E, Yorozu A, Ishiguro K, Sasaki H, Sudo G, Toyota M, Hatahira T, et al: UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells. Clin Epigenetics. 11:702019. View Article : Google Scholar : PubMed/NCBI


Fu Y, Cao T, Zou X, Ye Y, Liu Y, Peng Y, Deng T, Yin L and Li X: AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer. Oncogenesis. 12:12023. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

Volume 26 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Song Y, Liu H, Xian Q, Gui C, Xu M and Zhou Y: Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains (Review). Oncol Lett 26: 542, 2023
Song, Y., Liu, H., Xian, Q., Gui, C., Xu, M., & Zhou, Y. (2023). Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains (Review). Oncology Letters, 26, 542.
Song, Y., Liu, H., Xian, Q., Gui, C., Xu, M., Zhou, Y."Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains (Review)". Oncology Letters 26.6 (2023): 542.
Song, Y., Liu, H., Xian, Q., Gui, C., Xu, M., Zhou, Y."Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains (Review)". Oncology Letters 26, no. 6 (2023): 542.