Introduction
Ovarian cancer is the second most common gynecological cancer worldwide, accounting for ~3% of all female cancer cases, with the typical age of diagnosis being 63-years-old. It is challenging to diagnose ovarian cancer at an early stage, and this cancer has a poor prognosis, with a five-year survival rate of ~47% (1). In order to provide a foundation for detecting and treating ovarian cancer, studies investigating the etiology of the disease are required. Previously, a study by the London Research Institute (Cancer Research UK, London, UK) found helicase, POLQ-like (HELQ) to be a novel gene that prevents ovarian cancer (2). In this study, the possibility of ovarian cancer in mice was increased two-fold when a copy of the HELQ gene was missing. Even the deficiency of one copy could lead to the formation of an increased number of tumors in mice. According to this study, detection of HELQ gene deficiency may be adopted to screen for ovarian cancer patients among women in the future, if HELQ helicase performs the same role in humans and mice (2).
HELQ is a superfamily II DNA helicase that was first identified in the human and mouse genomes through its homology to mutagen-sensitive 308 (Mus308) (3), a DNA repair enzyme required for DNA interstrand crosslink (ICL) resistance in Drosophila melanogaster (4,5). DNA ICLs are particularly toxic as they disrupt genetic information on strands, potently inhibiting DNA replication and transcription. In normal cells, DNA ICLs and DNA damage often lead to the occurrence of cancer (6). However, DNA repair is an important reaction following DNA damage, which may cause the damaged DNA to revert to the original appearance and perform the original function (7). DNA helicases play an important role in this process. HELQ, as a DNA helicase, has been studied from the perspective of association with cancer. Previous genome-wide association studies have identified single nucleotide polymorphisms at loci within or near the HELQ gene that are associated with an increased risk of several different cancers, including upper aerodigestive tract cancers and head and neck cancers (8–11).
To assess the association between the structure of HELQ and the carcinogenesis of ovarian cancer, bioinformatics methods were used to analyze this association from a theoretical angle in the present study. It was expected that such a study may provide direction and basis for the clinical treatment of ovarian cancer.
Discussion
DNA helicases have crucial roles in maintaining genome stability and stable DNA replication in all organisms. They have been implicated in nucleotide excision repair, mismatch repair, base excision repair, double strand break repair and cross-link repair (14). The helicases PriA, RecG, RuvAB, RecBCD, UurD, Srs2, Rep and RecQ are well known for roles in promoting DNA repair and recombination by several possible mechanisms (15–17). Similar to RecQ, the Mus308 family of helicases supports genome stability. The Mus308 locus was identified in Drosophila melanogaster, being required for resistance to DNA crosslinking agents (4). Moldovan et al (18) found that the deletion of HEL308 in human cells could induce sensitivity to replication-blocking lesions, namely the ICLs induced by mitomycin C and irinotecan hydrochloride. Biochemical studies have established that human HEL308 is an ATP-dependent enzyme that unwinds DNA with a 3′-5′ polarity (3,19), which is consistent with the structure of HELQ containing ATP-binding sites found in the present study. In the functional domains of HELQ, Helicase_ATP-Bind_1 and Helicase_Cter locate in the center position and they mainly perform helicase activity. At the C-terminal, the helix-hairpin-helix configuration may be important for binding to DNA strands. The results of the functional protein association networks found that HELQ was involved in ubiquitination in the process of DNA repair. RTEL1 is responsible for the maintenance of chromosome ends and has a synergistic effect with proliferating cell nuclear antigen (PCNA) in the process of DNA replication to ensure cell growth and division, and to avoid genetic mistakes. When RTEL1 cannot combine with PCNA, DNA replication cannot continue and the errors produced lead to cancer (20). FAM175A mediates the formation of the BRCA1-RAP80 complex, which adds or modifies existing ubiquitin chains to promote DNA damage repair (21). SUMO1 is important in the control genomic integrity. Hu et al (22) found that SUMO1 repaired DNA lesions through an ubiquitin-like modification path. POLN works as a DNA polymerase and participates in DNA repair to make DNA replication proceed normally (18). However, the exact mechanism of HELQ remains unclear.
An increasing number of studies focus on the function exploration of HELQ. Ward et al (23) found that HELQ-1 played a role in meiotic double-strand break repair by promoting postsynaptic RAD-51 filament disassembly in Caenorhabditis elegans. Another study identified that in humans, HELQ was expressed in the ovaries, testes, heart and skeletal muscle (24). Luebben et al (25) reported that mammalian HELQ contributed to genome stability in unchallenged conditions through a mechanism distinct from the function of Fanconi anemia complementation group C. HELQ in humans requires additional investigation, particularly the association with cancer. The occurrence of tumors is usually closely associated with abnormal DNA replication and cell proliferation. Appropriate readjustment in the structure of HELQ to change its primary function may be used to alleviate DNA damage or promote DNA variation.
The genetic complexity of cancer has posed a challenge for devising successful therapeutic treatments. Tumor resistance to cytotoxic chemotherapy drugs and radiation, which induce DNA damage, has limited their effectiveness (26). Targeting the DNA damage response is one strategy for combating cancer. The prospect for success of chemotherapy treatment may be improved by the selective inactivation of a DNA repair pathway.
In conclusion, the structure of HELQ protein was predicted and analyzed in this study. Its unique structural characteristics will have an important role in future investigations of HELQ gene deletion, as well as the etiological analysis and targeted therapy of ovarian cancer.