Xrcc6-KO Mouse

XRCC6, also known as Ku70, is a gene encoding a protein that plays a crucial role in the DNA non-homologous end-joining (NHEJ) pathway. The NHEJ pathway is the main mechanism for repairing DNA double-strand breaks (DSBs) in human cells, which is essential for maintaining genomic stability and preventing carcinogenesis [3].

A meta-analysis of 13 case-control studies indicated that the XRCC6 rs2267437 polymorphism was associated with cancer susceptibility, especially in breast cancer, Asian populations, and population-based studies [1]. Another meta-analysis of 20 case-control studies found that the rs2267437 polymorphism increased the risks of overall cancers, breast cancer, renal cell carcinoma, and hepatocellular carcinoma, and the rs5751129 polymorphism increased the risk of overall cancers [2]. In nasopharyngeal carcinoma (NPC), the TC and CC genotypes of XRCC6 promoter T-991C (rs5751129) were associated with a significantly increased risk, and the mRNA and protein expression levels were lower in NPC samples with these genotypes [4]. Similar results were found in hepatocellular carcinoma in Taiwanese population, where the TC and CC genotypes of the same polymorphism conferred a significantly increased risk of HCC, and the mRNA and protein expressions were lower in samples with these genotypes [6]. In a study of esophageal squamous cell carcinoma (ESCC) in North China, the CG carriers and G allele carriers of rs2267437 (XRCC6) were at higher risk of ESCC [8]. In contrast, in the Polish population, the XRCC6 C1310G polymorphism was associated with a decreased risk of colorectal cancer [9]. In osteosarcoma, high expression of XRCC6 promoted cell proliferation through the β-catenin/Wnt signaling pathway and was associated with poor prognosis [10]. Also, in male infertility, the mutant GG genotypes and carriers of the CG and GG genotypes of XRCC6-61C>G showed increased risk [5]. In biochemical premature ovarian insufficiency, miR-379-5p overexpression inhibited granulosa cell proliferation and attenuated DNA repair efficiency, and XRCC6 was identified as one of its targets [7].

In conclusion, XRCC6 is crucial for DNA double-strand break repair through the NHEJ pathway, maintaining genomic stability. Studies on XRCC6 gene polymorphisms and expression levels have revealed its significant associations with various cancers, male infertility, and biochemical premature ovarian insufficiency. These findings enhance our understanding of the role of XRCC6 in disease development, potentially providing new targets for disease diagnosis, treatment, and prevention.

References:

1. Xu, Haitao, Zou, Peng, Chen, Pin, Zhao, Peng, Lu, Ailin. 2013. Association between the XRCC6 Promoter rs2267437 polymorphism and cancer risk: evidence based on the current literature. In Genetic testing and molecular biomarkers, 17, 607-14. doi:10.1089/gtmb.2013.0083. https://pubmed.ncbi.nlm.nih.gov/23745766/

2. Jia, Jing, Ren, Juan, Yan, Dongmei, Xiao, Long, Sun, Ruifen. . Association between the XRCC6 polymorphisms and cancer risks: a systematic review and meta-analysis. In Medicine, 94, e283. doi:10.1097/MD.0000000000000283. https://pubmed.ncbi.nlm.nih.gov/25569644/

3. Bau, Da-Tian, Tsai, Chia-Wen, Wu, Cheng-Nan. . Role of the XRCC5/XRCC6 dimer in carcinogenesis and pharmacogenomics. In Pharmacogenomics, 12, 515-34. doi:10.2217/pgs.10.209. https://pubmed.ncbi.nlm.nih.gov/21521024/

4. Huang, C-Y, Tsai, C-W, Hsu, C-M, Shui, H-A, Bau, D-T. 2015. The role of XRCC6/Ku70 in nasopharyngeal carcinoma. In International journal of oral and maxillofacial surgery, 44, 1480-5. doi:10.1016/j.ijom.2015.06.008. https://pubmed.ncbi.nlm.nih.gov/26149939/

5. Jahantigh, Danial, Hosseinzadeh Colagar, Abasalt. 2017. XRCC5 VNTR, XRCC6 -61C>G, and XRCC7 6721G>T Gene Polymorphisms Associated with Male Infertility Risk: Evidences from Case-Control and In Silico Studies. In International journal of endocrinology, 2017, 4795076. doi:10.1155/2017/4795076. https://pubmed.ncbi.nlm.nih.gov/28421111/

6. Hsu, Chin-Mu, Yang, Mei-Due, Chang, Wen-Shin, Tsai, Fuu-Jen, Bau, Da-Tian. . The contribution of XRCC6/Ku70 to hepatocellular carcinoma in Taiwan. In Anticancer research, 33, 529-35. doi:. https://pubmed.ncbi.nlm.nih.gov/23393345/

7. Dang, Yujie, Wang, Xiaoyan, Hao, Yajing, Qin, Yingying, Chen, Zi-Jiang. 2018. MicroRNA-379-5p is associate with biochemical premature ovarian insufficiency through PARP1 and XRCC6. In Cell death & disease, 9, 106. doi:10.1038/s41419-017-0163-8. https://pubmed.ncbi.nlm.nih.gov/29367615/

8. Li, Kun, Yin, Xiuli, Yang, Hongli, Xu, Changqing, Xu, Hongwei. 2015. Association of the genetic polymorphisms in XRCC6 and XRCC5 with the risk of ESCC in a high-incidence region of North China. In Tumori, 101, 24-9. doi:10.5301/tj.5000206. https://pubmed.ncbi.nlm.nih.gov/25702660/

9. Balinska, Kinga, Wilk, Damian, Filipek, Beata, Kabziński, Jacek, Majsterek, Ireneusz. . Association of XRCC6 C1310G and LIG4 T9I polymorphisms of NHEJ DNA repair pathway with risk of colorectal cancer in the Polish population. In Polski przeglad chirurgiczny, 91, 15-20. doi:10.5604/01.3001.0013.1030. https://pubmed.ncbi.nlm.nih.gov/31243170/

10. Zhu, Bin, Cheng, Dongdong, Li, Shijie, Zhou, Shumin, Yang, Qingcheng. 2016. High Expression of XRCC6 Promotes Human Osteosarcoma Cell Proliferation through the β-Catenin/Wnt Signaling Pathway and Is Associated with Poor Prognosis. In International journal of molecular sciences, 17, . doi:10.3390/ijms17071188. https://pubmed.ncbi.nlm.nih.gov/27455247/