The DNA replication machinery invariably encounters obstacles that slow replication fork progression, and threaten to prevent complete replication and faithful segregation of sister chromatids. The resulting replication stress activates ATR, the major kinase involved in resolving impaired DNA replication. In addition, replication stress also activates the related kinase ATM, which is required to prevent mitotic segregation errors. However, the molecular mechanism of ATM activation by replication stress is not defined. Here we show that monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA), a marker of stalled replication forks, interacts with the ATM cofactor ATMIN via WRN interacting protein 1 (WRNIP1). ATMIN, WRNIP1 and RAD18, the E3 ligase responsible for PCNA monoubiquitination, are specifically required for ATM signalling and 53BP1 focus formation induced by replication stress, not ionising radiation. Thus, WRNIP1 connects PCNA monoubiquitination with ATMIN/ATM to activate ATM signalling in response to replication stress and contribute to the maintenance of genomic stability.

ABSTRACT. We conducted a prospective study to investigate whether ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 gene polymorphisms could serve as potential biomarkers for the prognosis of gastric cancer. Between January 2010 and December 2012, 246 patients with pathologically proven gastric cancer who were receiving platinum-based chemotherapy were recruited from the First Affiliated Hospital of Guangxi Medical University. The genotyping of the gene polymorphisms was conducted using the polymerase chain reaction coupled with restriction fragment length polymorphism. By logistic regression analysis, we found that the AA genotype of ERCC1 rs3212986 was associated with lower rates of complete remission and partial remission following chemotherapy in gastric cancer patients, and the OR (95%CI) was 0.19 (0.06-0.60). We found that the AA genotype of rs3212986 was correlated with higher risk of death from gastric cancer according to the Cox proportional hazards model, and the adjusted HR (95%CI) was 1.60 (0.81-3.16). However, we found no association between ERCC1 rs11615, ERCC2 rs13181, and ERCC2 rs1799793 and overall survival of gastric cancer. In conclusion, the results of the present retrospective study indicate that the ERCC1 rs3212986 gene polymorphism has a significant effect on the pharmacokinetics and treatment outcome of gastric cancer.