XAB2 TagSNP Is Associated with the Risk of Gastric Cancer in Chinese Population: A Case–Control Study

XAB2 protein (xeroderma pigmentosum group A-binding protein 2) plays a significant role in the nucleotide excision repair pathway. Polymorphisms in the XAB2 gene may have an effect on the capability of DNA repair and further contribute to the risk of developing various cancers. In order to investigate the relationship between XAB2 genetic variants and the risk of gastric cancer, we performed a hospital-based case–control study. XAB2 tagSNPs were selected and then genotyped by iPlex Gold Genotyping Assay and Sequenom MassArray. By performing logistic regression analysis, odds ratio (OR) and 95% confidence interval (CI) were used to estimate the association of XAB2 tagSNPs with the risk of gastric cancer. Our results showed that XAB2 rs794078AA genotype was associated with a significantly lower risk of gastric cancer compared with GG genotype with OR (95% CI) of 0.33 (0.12–0.91). Stratified analysis indicated a significantly decreased risk for gastric cancer among smokers with rs794078AA genotype compared with nonsmokers with GG genotype (OR = 0.11, 95% CI = 0.01–0.91, p = 0.040). The gene–gene interactions by multifactor dimensionality reduction (MDR) showed that tagSNP rs794078 was the best predictive element for gastric cancers (Testing Bal. Acc = 51.68%, p = 0.055, cross-validation consistency = 9). Therefore, the XAB2 tagSNP rs794078 may play an important role in the development of gastric cancer.

XAB2 TagSNP is Associated with the Risk of Gastric Cancer in Chinese Population:a case-control study

Background: XAB2 protein (xeroderma pigmentosum group A-binding protein 2) plays a significant role in the nucleotide excision repair pathway and transcription coupled DNA repair. Polymorphisms in XAB2 gene may effect on the capability of DNA repair and further contribute to the risk of developing various cancers. Methods: in order to investigate the relationship between XAB2 genetic variants and the risk of gastric cancer, we performed a hospital-based case-control study. XAB2 tagSNPs were genotyped by using iPlex Gold Genotyping Asssy and Sequenom MassArray. By conducting logistic regression, odds ratio (OR) and 95% confidence interval (CI) were used to represent the association of XAB2 tagSNPs with the risk of gastric cancer. Results: Our results showed that XAB2 rs794078 AA genotype was associated with a significantly lower risk of gastric cancer compared with GG genotype with OR (95%CI) of 0.33(0.12-0.91). Stratified analysis indicated a significantly decreased risk for gastric cancer among smokers with rs794078 AA genotype compared with non-smokers with GG genotype (OR=0.11, 95%CI=0.01-0.91, P=0.040). The gene-gene interactions by multifactor dimensionality reduction (MDR) showed that tagSNP rs794078 was the best predictive elements for gastric cancers (Testing Bal. Acc=51.68%, P=0.055, cross-validation consistency=9). Conclusion: The XAB2 tagSNP rs794078 were significantly associated with the risk of gastric cancer in Chinese population, which proved the important role of XAB2 in the development of gastric cancer.

Transactivation domain of p53 regulates DNA repair and integrity in human iPS cells

The role of p53 transactivation domain (p53-TAD), a multifunctional and dynamic domain, on DNA repair and retaining DNA integrity in human induced pluripotent stem cells (hiPSCs) has never been studied. p53-TAD was knocked out in iPSCs using CRISPR/Cas9 and was confirmed by DNA sequencing. p53-TAD knockout (KO) cells were characterized by accelerated proliferation, decreased population doubling time, and unaltered Bcl-2, Bcl-2-binding component 3, insulin-like growth factor 1 receptor, and Bax and altered Mdm2, p21, and p53-induced death domain transcript expression. In p53-TAD KO cells, the p53-regulated DNA repair proteins xeroderma pigmentosum group A, DNA polymerase H, and DNA-binding protein 2 expression were found to be reduced compared with p53 wild-type cells. Exposure to a low dose of doxorubicin (Doxo) induced similar DNA damage and DNA damage response (DDR) as measured by RAD50 and MRE11 expression, checkpoint kinase 2 activation, and γH2A.X recruitment at DNA strand breaks in both cell groups, indicating that silence of p53-TAD does not affect the DDR mechanism upstream of p53. After removal of Doxo, p53 wild-type hiPSCs underwent DNA repair, corrected their damaged DNA, and restored DNA integrity. Conversely, p53-TAD KO hiPSCs did not undergo complete DNA repair and failed to restore DNA integrity. More importantly, continuous culture of p53-TAD KO hiPSCs underwent G2/M cell cycle arrest and expressed the cellular senescent marker p16INK4a. Our data clearly show that silence of the TAD of p53 did not affect DDR but affected the DNA repair process, implying the crucial role of p53-TAD in maintaining DNA integrity. Therefore, activating p53-TAD domain using small molecules may promote DNA repair and integrity of cells and prevent cellular senescence. NEW & NOTEWORTHY The p53 transactivation domain (TAD) in human induced pluripotent stem cells (iPSCs) was deleted using the CRISPR/Cas9 system. Deletion of p53-TAD resulted in increased cell proliferation but did not affect iPSC pluripotency. DNA repair machinery upstream of p53 was not affected in p53-TAD knockout, but p53-regulated DNA repair proteins xeroderma pigmentosum group A, DNA polymerase H, and DNA-binding protein 2 were affected. Finally, p53-TAD was found to be necessary for iPSCs to repair damaged DNA and retain DNA integrity.