Search

Base excision repair (BER) is the main mechanism to repair endogenous DNA lesions caused by reactive oxygen species. BER deficiency is linked with cancer susceptibility and premature aging. Single nucleotide polymorphisms (SNPs) within BER genes have been implicated in various human malignancies. Nevertheless, a comprehensive investigation of their association with Wilms tumor susceptibility is lacking. In this study, 145 cases and 531 sex and age-matched healthy controls were recruited. We systematically genotyped 18 potentially functional SNPs in six core BER pathway genes, using a candidate SNP approach. Logistic regression was employed to evaluate odds ratio (OR) and 95% confidence interval (CI) adjusted for age and gender. Several SNPs showed protective effects against Wilms tumor. Significant associations with Wilms tumor susceptibility were shown for hOGG1 rs1052133 (dominant: adjusted OR = 0.66, 95% CI = 0.45–0.96, P = .030), FEN1 rs174538 (dominant: adjusted OR = 0.66, 95% CI = 0.45–0.95, P = .027; recessive: adjusted OR = 0.54, 95% CI = 0.32–0.93 P = .027), and FEN1 rs4246215 (dominant: adjusted OR = 0.55, 95% CI = 0.38–0.80, P = .002) polymorphisms. Stratified analysis was performed by age, gender, and clinical stage. Moreover, there was evidence of functional implication of these significant SNPs suggested by online expression quantitative trait locus (eQTL) analysis. Our findings indicate that common SNPs in BER genes modify susceptibility to Wilms tumor., Highlights • Numerous studies demonstrated association between BER gene SNPs and cancer susceptibility. However, the linkage between BER SNPs and Wilms tumor susceptibility has not been reported. We investigated 18 BER gene SNPs in 145 Wilms tumor cases and 531 healthy controls. Significant associations with decreased Wilms tumor susceptibility were observed for the hOGG1 rs1052133, FEN1 rs174538, and rs4246215 polymorphisms. eQTL analysis suggested potential functional implications for the significant polymorphisms. This is the most comprehensive investigations on the association between the BER polymorphisms and Wilms tumor susceptibility. Our findings support the potential protective role of these SNPs in Wilms tumor.

Cancer cells frequently up-regulate DNA replication and repair proteins such as the multifunctional DNA2 nuclease/helicase, counteracting DNA damage due to replication stress and promoting survival. Therefore, we hypothesized that blocking both DNA replication and repair by inhibiting the bifunctional DNA2 could be a potent strategy to sensitize cancer cells to stresses from radiation or chemotherapeutic agents. We show that homozygous deletion of DNA2 sensitizes cells to ionizing radiation and camptothecin (CPT). Using a virtual high throughput screen, we identify 4-hydroxy-8-nitroquinoline-3-carboxylic acid (C5) as an effective and selective inhibitor of DNA2. Mutagenesis and biochemical analysis define the C5 binding pocket at a DNA-binding motif that is shared by the nuclease and helicase activities, consistent with structural studies that suggest that DNA binding to the helicase domain is necessary for nuclease activity. C5 targets the known functions of DNA2 in vivo: C5 inhibits resection at stalled forks as well as reducing recombination. C5 is an even more potent inhibitor of restart of stalled DNA replication forks and over-resection of nascent DNA in cells defective in replication fork protection, including BRCA2 and BOD1L. C5 sensitizes cells to CPT and synergizes with PARP inhibitors., Highlights • C5 binds to the helicase domain of DNA2 and inhibits its nuclease, ATPase, and helicase activities. • C5 inhibits DNA end resection for DNA double strand break repair and restart of stalled replication forks. • C5 suppresses over-resection of nascent DNA in cells defective in fork protection. • C5 sensitizes cancer cells to chemotherapeutic agents. Most chemotherapeutics introduce DNA lesions that block DNA replication to kill cancer cells. Upregulation of DNA repair proteins in cancer cells is a major reason for human cancer to become resistant to chemotherapeutics. DNA repair proteins such as DNA2 nuclease/helicase have long been proposed as targets for sensitization of cancer cells to chemotherapy. We identify a selective DNA2 inhibitor (C5) and demonstrate that DNA2 inhibition by C5 suppresses cancer cells to rescue stalled replication forks. Consequently, it sensitizes cancer cells to replication fork stalling agents such as camptothecin. Thus, C5 is a promising lead compound for developing new anticancer drugs.