Structure-function analysis of DNA helicase HELQ: A new diagnostic marker in ovarian cancer

Li,Ya‑Ping; Yang,Jun‑Juan; Xu,Hui; Guo,En‑Yu; Yu,Yan

doi:10.3892/ol.2016.5224

Structure-function analysis of DNA helicase HELQ: A new diagnostic marker in ovarian cancer

Authors:
- Ya‑Ping Li
- Jun‑Juan Yang
- Hui Xu
- En‑Yu Guo
- Yan Yu
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Affiliations: School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Obstetrics and Gynecology, Women & Infants Hospital of Zhengzhou, Zhengzhou, Henan 450053, P.R. China, Department of Obstetrics and Gynecology, Zhengzhou People's Hospital, Zhengzhou, Henan 450003, P.R. China, Department of Equipment, Zhengzhou People's Hospital, Zhengzhou, Henan 450003, P.R. China
Published online on: October 5, 2016 https://doi.org/10.3892/ol.2016.5224
Pages: 4439-4444
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has been previously reported that a deficiency of the helicase, POLQ-like (HELQ) gene increases the risk of ovarian cancer. The present study aimed to explore the structure‑function association of HELQ and discuss the effect of molecular structure on the occurrence of tumors. ExPASy tools were employed to analyze the physicochemical properties and secondary structure of the genes. PHYRE2 Protein Fold Recognition Server was used to construct the three-dimensional model and find the ligand‑binding sites of HELQ. In addition, the potential functions corresponding to these structures were excavated by comparing and analyzing protein domains. The HELQ protein is located in the cytoplasm (56.5%) and nucleus (21.7%). HELQ has 4 conserved domains, consisting of DEXDc, HELICc, HHH_5 and PRK02362, which contain the adenosine triphosphate (ATP) binding site, nucleotide binding region and putative Mg2+ binding site. In the secondary structure, it was found that HELQ was mainly composed of α helix (46.68%) and random coils (43.05%), with only 10.26% extended strand. According to 3DLigandSite Server, the ligand binding sites appeared in ILE333, LYS335, TYR337, SER362, LEU367, LYS397, GLN340, GLY363, GLY364 and ASN678 of the amino acid sequence. Among the functional protein association networks, regulator of telomere elongation helicase 1, family with sequence similarity 175 member A, small ubiquitin‑like modifier 1, DNA polymerase ν and coiled‑coil domain containing 158 were involved and co‑expressed with HELQ. PredictProtein analysis indicated that the dominant functions of HELQ were ATP‑dependent helicase activity and participation in the DNA repair process. Characteristics of the HELQ protein were obtained by bioinformatics analysis, based on which the role of HELQ in DNA replication, DNA repair and maintenance of genomic stability was explored. It was concluded that modulation the function of HELQ helicase may be used in the treatment of ovarian cancer.

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1	Thomson CA, E Crane T, Wertheim BC, Neuhouser ML, Li W, Snetselaar LG, Basen-Engquist KM, Zhou Y and Irwin ML: Diet quality and survival after ovarian cancer: Results from the Women's health initiative. J Natl Cancer Inst. 106:dju3142014. View Article : Google Scholar : PubMed/NCBI
2	Adelman CA, Lolo RL, Birkbak NJ, Murina O, Matsuzaki K, Horejsi Z, Parmar K, Borel V, Skehel JM, Stamp G, et al: HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis. Nature. 502:381–384. 2013. View Article : Google Scholar : PubMed/NCBI
3	Marini F and Wood RD: A human DNA helicase homologous to the DNA cross-link sensitivity protein Mus308. J Biol Chem. 277:8716–8723. 2002. View Article : Google Scholar : PubMed/NCBI
4	Boyd JB, Sakaguchi K and Harris PV: mus308 mutants of Drosophila exhibit hypersensitivity to DNA cross-linking agents and are defective in a deoxyribonuclease. Genetics. 125:813–819. 1990.PubMed/NCBI
5	Leonhardt EA, Henderson DS, Rinehart JE and Boyd JB: Characterization of the mus308 gene in Drosophila melanogaster. Genetics. 133:87–96. 1993.PubMed/NCBI
6	Dolgova EV, Alyamkina EA, Efremov YR, Nikolin VP, Popova NA, Tyrinova TV, Kozel AV, Minkevich AM, Andrushkevich OM, Zavyalov EL, et al: Identification of cancer stem cells and a strategy for their elimination. Cancer Biol Ther. 15:1378–1394. 2014. View Article : Google Scholar : PubMed/NCBI
7	Roy S: Maintenance of genome stability in plants: Repairing DNA double strand breaks and chromatin structure stability. Front Plant Sci. 5:4872014. View Article : Google Scholar : PubMed/NCBI
8	Li WQ, Hu N, Hyland PL, Gao Y, Wang ZM, Yu K, Su H, Wang CY, Wang LM, Chanock SJ, et al: Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population. Carcinogenesis. 34:1536–1542. 2013. View Article : Google Scholar : PubMed/NCBI
9	Gao Y, He Y, Xu J, Xu L, Du J, Zhu C, Gu H, Ma H, Hu Z, Jin G, et al: Genetic variants at 4q21, 4q23 and 12q24 are associated with esophageal squamous cell carcinoma risk in a Chinese population. Human Genet. 132:649–656. 2013. View Article : Google Scholar
10	Liang C, Marsit CJ, Houseman EA, Butler R, Nelson HH, McClean MD and Kelsey KT: Gene-environment interactions of novel variants associated with head and neck cancer. Head Neck. 34:1111–1118. 2012. View Article : Google Scholar : PubMed/NCBI
11	McKay JD, Truong T, Gaborieau V, Chabrier A, Chuang SC, Byrnes G, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Lissowska J, et al: A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet. 7:e10013332011. View Article : Google Scholar : PubMed/NCBI
12	Käll L, Krogh A and Sonnhammer EL: A combined transmembrane topology and signal peptide prediction method. J Mol Biol. 338:1027–1036. 2004. View Article : Google Scholar : PubMed/NCBI
13	Scott L, Chahine J and Ruggiero J: Prediction of Protein Structures using a Hopfield NetworkSixth Brazilian Symposium on Neural Networks 2000. IEEE Computer Society Press; Washington, DC: pp. 284. 2000, View Article : Google Scholar
14	McGlynn P: Helicases at the replication fork. Adv Exp Med Biol. 767:97–121. 2013. View Article : Google Scholar : PubMed/NCBI
15	Tsang E and Carr AM: Replication fork arrest, recombination and the maintenance of ribosomal DNA stability. DNA repair (Amst). 7:1613–1623. 2008. View Article : Google Scholar : PubMed/NCBI
16	McGlynn P and Lloyd RG: Recombinational repair and restart of damaged replication forks. Nat Rev Mol Cell Biol. 3:859–870. 2002. View Article : Google Scholar : PubMed/NCBI
17	Singleton MR and Wigley DB: Modularity and specialization in superfamily 1 and 2 helicases. J Bacteriol. 184:1819–1826. 2002. View Article : Google Scholar : PubMed/NCBI
18	Moldovan GL, Madhavan MV, Mirchandani KD, McCaffrey RM, Vinciguerra P and D'Andrea AD: DNA polymerase POLN participates in cross-link repair and homologous recombination. Mol Cell Biol. 30:1088–1096. 2010. View Article : Google Scholar : PubMed/NCBI
19	Tafel AA, Wu L and McHugh PJ: Human HEL308 localizes to damaged replication forks and unwinds lagging strand structures. J Biol Chem. 286:15832–15840. 2011. View Article : Google Scholar : PubMed/NCBI
20	Vannier JB, Sandhu S, Petalcorin MI, Wu X, Nabi Z, Ding H and Boulton SJ: RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication. Science. 342:239–242. 2013. View Article : Google Scholar : PubMed/NCBI
21	Coleman KA and Greenberg RA: The BRCA1-RAP80 complex regulates DNA repair mechanism utilization by restricting end resection. J Biol Chem. 286:13669–13680. 2011. View Article : Google Scholar : PubMed/NCBI
22	Hu Y and Parvin JD: Small ubiquitin-like modifier (SUMO) isoforms and conjugation-independent function in DNA double-strand break repair pathways. J Biol Chem. 289:21289–21295. 2014. View Article : Google Scholar : PubMed/NCBI
23	Ward JD, Muzzini DM, Petalcorin MI, Martinez-Perez E, Martin JS, Plevani P, Cassata G, Marini F and Boulton SJ: Overlapping mechanisms promote postsynaptic RAD-51 filament disassembly during meiotic double-strand break repair. Mol Cell. 37:259–272. 2010. View Article : Google Scholar : PubMed/NCBI
24	Marini F, Kim N, Schuffert A and Wood RD: POLN, a nuclear PolA family DNA polymerase homologous to the DNA cross-link sensitivity protein Mus308. J Biol Chem. 278:32014–32019. 2003. View Article : Google Scholar : PubMed/NCBI
25	Luebben SW, Kawabata T, Akre MK, Lee WL, Johnson CS, O'Sullivan MG and Shima N: Helq acts in parallel to Fancc to suppress replication-associated genome instability. Nucleic Acids Res. 41:10283–10297. 2013. View Article : Google Scholar : PubMed/NCBI
26	Kelley MR and Fishel ML: DNA repair proteins as molecular targets for cancer therapeutics. Anticancer Agents Med Chem. 8:417–425. 2008. View Article : Google Scholar : PubMed/NCBI