Ubiquitin‑like protein FAT10 regulates DNA damage repair via modification of proliferating cell nuclear antigen

Chen,Zhenchuan; Zhang,Wei; Yun,Zhimin; Zhang,Xue; Gong,Feng; Wang,Yunfang; Ji,Shouping; Leng,Ling

doi:10.3892/mmr.2018.8843

Ubiquitin‑like protein FAT10 regulates DNA damage repair via modification of proliferating cell nuclear antigen

Authors:
- Zhenchuan Chen
- Wei Zhang
- Zhimin Yun
- Xue Zhang
- Feng Gong
- Yunfang Wang
- Shouping Ji
- Ling Leng
View Affiliations

Affiliations: Stem Cell and Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing 100850, P.R. China
Published online on: April 5, 2018 https://doi.org/10.3892/mmr.2018.8843
Pages: 7487-7496
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In response to DNA damage, proliferating cell nuclear antigen (PCNA) has an important role as a positive regulator and as a scaffold protein associated with DNA damage bypass and repair pathways by serving as a platform for the recruitment of associated components. As demonstrated in the present study, the ubiquitin‑like modifier human leukocyte antigen F locus adjacent transcript 10 (FAT10), which binds to PCNA but has not previously been demonstrated to be associated with the DNA damage response (DDR), is induced by ultraviolet/ionizing radiation and VP‑16 treatment in HeLa cells. Furthermore, DNA damage enhances FAT10 expression. Immunoprecipitation analysis suggested PCNA is modified by FAT10, and the degradation of FATylated PCNA located in the cytoplasm is regulated by the 26S proteasome, which is also responsible for the upregulation of nuclear foci formation. Furthermore, immunofluorescence experiment suggested FAT10 co‑localizes with PCNA in nuclear foci, thus suggesting that FATylation of PCNA may affect DDR via the induction of PCNA degradation in the cytoplasm or nucleus. In addition, immunohistochemistry experiment suggested the expression levels of FAT10 and PCNA are enhanced in HCC tissues compared with healthy liver tissues; however, the expression of FAT10 is suppressed in regenerated liver tissues, which express high levels of PCNA, thus suggesting that the association between FAT10 and PCNA expression is only exhibited in tumor tissues. In conclusion, the results of the present study suggest that FAT10 may be involved in DDR and therefore the progression of tumorigenesis.

View Figures

View References

1	Ren J, Kan A, Leong SH, Ooi LL, Jeang KT, Chong SS, Kon OL and Lee CG: FAT10 plays a role in the regulation of chromosomal stability. J Biol Chem. 281:11413–11421. 2006. View Article : Google Scholar : PubMed/NCBI
2	Snyder A, Alsauskas Z, Gong P, Rosenstiel PE, Klotman ME, Klotman PE and Ross MJ: FAT10: A novel mediator of Vpr-induced apoptosis in human immunodeficiency virus-associated nephropathy. J Virol. 83:11983–11988. 2009. View Article : Google Scholar : PubMed/NCBI
3	Terai K, Abbas T, Jazaeri AA and Dutta A: CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Mol Cell. 37:143–149. 2010. View Article : Google Scholar : PubMed/NCBI
4	Hipp MS, Kalveram B, Raasi S, Groettrup M and Schmidtke G: FAT10, a ubiquitin-independent signal for proteasomal degradation. Mol Cell Biol. 25:3483–3491. 2005. View Article : Google Scholar : PubMed/NCBI
5	Aichem A and Groettrup M: The ubiquitin-like modifier FAT10 in cancer development. Int J Biochem Cell Biol. 79:451–461. 2016. View Article : Google Scholar : PubMed/NCBI
6	Canaan A, Yu X, Booth CJ, Lian J, Lazar I, Gamfi SL, Castille K, Kohya N, Nakayama Y, Liu YC, et al: FAT10/diubiquitin-like protein-deficient mice exhibit minimal phenotypic differences. Mol Cell Biol. 26:5180–5189. 2006. View Article : Google Scholar : PubMed/NCBI
7	Canaan A, DeFuria J, Perelman E, Schultz V, Seay M, Tuck D, Flavell RA, Snyder MP, Obin MS and Weissman SM: Extended lifespan and reduced adiposity in mice lacking the FAT10 gene. Proc Natl Acad Sci USA. 111:5313–5318. 2014. View Article : Google Scholar : PubMed/NCBI
8	Lee CG, Ren J, Cheong IS, Ban KH, Ooi LL, Tan Yong S, Kan A, Nuchprayoon I, Jin R, Lee KH, et al: Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers. Oncogene. 22:2592–2603. 2003. View Article : Google Scholar : PubMed/NCBI
9	Zhang DW, Jeang KT and Lee CG: p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers. Oncogene. 25:2318–2327. 2006. View Article : Google Scholar : PubMed/NCBI
10	Leng L, Xu C, Wei C, Zhang J, Liu B, Ma J, Li N, Qin W, Zhang W, Zhang C, et al: A proteomics strategy for the identification of FAT10-modified sites by mass spectrometry. J Proteome Res. 13:268–276. 2014. View Article : Google Scholar : PubMed/NCBI
11	Moldovan GL, Pfander B and Jentsch S: PCNA, the maestro of the replication fork. Cell. 129:665–679. 2007. View Article : Google Scholar : PubMed/NCBI
12	Kannouche PL, Wing J and Lehmann AR: Interaction of human DNA polymerase eta with monoubiquitinated PCNA: A possible mechanism for the polymerase switch in response to DNA damage. Mol Cell. 14:491–500. 2004. View Article : Google Scholar : PubMed/NCBI
13	de Medina-Redondo M and Meraldi P: The spindle assembly checkpoint: Clock or domino? Results Probl Cell Differ. 53:75–91. 2011. View Article : Google Scholar : PubMed/NCBI
14	Lindahl T and Barnes DE: Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol. 65:127–133. 2000. View Article : Google Scholar : PubMed/NCBI
15	Mailand N, Gibbs-Seymour I and Bekker-Jensen S: Regulation of PCNA-protein interactions for genome stability. Nat Rev Mol Cell Biol. 14:269–282. 2013. View Article : Google Scholar : PubMed/NCBI
16	Brown JS and Jackson SP: Ubiquitylation, neddylation and the DNA damage response. Open Biol. 5:1500182015. View Article : Google Scholar : PubMed/NCBI
17	Gibbs-Seymour I, Oka Y, Rajendra E, Weinert BT, Passmore LA, Patel KJ, Olsen JV, Choudhary C, Bekker-Jensen S and Mailand N: Ubiquitin-SUMO circuitry controls activated fanconi anemia ID complex dosage in response to DNA damage. Mol Cell. 57:150–164. 2015. View Article : Google Scholar : PubMed/NCBI
18	Park JM, Yang SW, Yu KR, Ka SH, Lee SW, Seol JH, Jeon YJ and Chung CH: Modification of PCNA by ISG15 plays a crucial role in termination of error-prone translesion DNA synthesis. Mol Cell. 54:626–638. 2014. View Article : Google Scholar : PubMed/NCBI
19	He M, Zhou W, Li C and Guo M: MicroRNAs, DNA Damage Response, and Cancer Treatment. Int J Mol Sci. 17:pii: E2087. 2016. View Article : Google Scholar
20	Tian H, Gao Z, Li H, Zhang B, Wang G, Zhang Q, Pei D and Zheng J: DNA damage response-a double-edged sword in cancer prevention and cancer therapy. Cancer Lett. 358:8–16. 2015. View Article : Google Scholar : PubMed/NCBI
21	Hershko A, Ciechanover A and Varshavsky A: Basic Medical Research Award. The ubiquitin system. Nat Med. 6:1073–1081. 2000. View Article : Google Scholar : PubMed/NCBI
22	Hoege C, Pfander B, Moldovan GL, Pyrowolakis G and Jentsch S: RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature. 419:135–141. 2002. View Article : Google Scholar : PubMed/NCBI
23	Bienko M, Green CM, Crosetto N, Rudolf F, Zapart G, Coull B, Kannouche P, Wider G, Peter M, Lehmann AR, et al: Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science. 310:1821–1824. 2005. View Article : Google Scholar : PubMed/NCBI
24	Mukhopadhyay D and Riezman H: Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science. 315:201–205. 2007. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Lanton T, Shriki A, Nechemia-Arbely Y, et al: IL6-dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis. Hepatology. 2016.
27	Buchsbaum S, Bercovich B and Ciechanover A: FAT10 is a proteasomal degradation signal that is itself regulated by ubiquitination. Mol Biol Cell. 23:225–232. 2012. View Article : Google Scholar : PubMed/NCBI
28	Aichem A, Kalveram B, Spinnenhirn V, Kluge K, Catone N, Johansen T and Groettrup M: The proteomic analysis of endogenous FAT10 substrates identifies p62/SQSTM1 as a substrate of FAT10ylation. J Cell Sci. 125:4576–4585. 2012. View Article : Google Scholar : PubMed/NCBI
29	Lim CB, Zhang D and Lee CG: FAT10, a gene up-regulated in various cancers, is cell-cycle regulated. Cell Div. 1:202006. View Article : Google Scholar : PubMed/NCBI
30	Schmidtke G, Kalveram B and Groettrup M: Degradation of FAT10 by the 26S proteasome is independent of ubiquitylation but relies on NUB1L. FEBS Lett. 583:591–594. 2009. View Article : Google Scholar : PubMed/NCBI