Deficiency of X‐ray repair cross‐complementing group 1 in primordial germ cells contributes to male infertility

Abstract

X‐ray repair cross‐complementing group 1 (Xrcc1), a key DNA repair gene, plays a vital role in maintaining genomic stability and is highly expressed in the early stages of spermatogenesis, but the exact functions remain elusive. Here we generated primordial germ cell–specific Xrcc1 knockout (cXrcc1−/−) mice to elucidate the effects of Xrcc1 on spermatogenesis. We demonstrated that Xrcc1 deficiency results in infertility in male mice due to impaired spermatogenesis. We found that cXrcc1−/− mice exhibited smaller size of testes as well as lower sperm concentration and motility than the wild‐type mice. Mechanistically, we demonstrated that Xrcc1 deficiency in primordial germ cells induced elevated levels of reactive oxygen species, mitochondria dysfunction, apoptosis, and loss of stemness of spermatogonial stem cells (SSCs) in testes. In Xrcc1‐deficienct SSCs, elevated oxidative stress and mitochondrial dysfunction could be partially reversed by treatment with the antioxidant N‐acetylcysteine (NAC), whereas NAC treatment did not restore the fertility or ameliorate the apoptosis caused by loss of Xrcc1. Overall, our findings provided new insights into understanding the crucial role of Xrcc1 during spermatogenesis.—Xu, C., Xu, J., Ji, G., Liu, Q., Shao, W., Chen, Y., Gu, J., Weng, Z., Zhang, X., Wang, Y., Gu, A. Deficiency of X‐ray repair cross‐complementing group 1 in primordial germ cells contributes to male infertility. FASEB J. 33, 7427–7436 (2019). http://www.fasebj.org

Association of XRCC1 and ERCC2 promoters’ methylation with chromatin condensation and sperm DNA fragmentation in idiopathic oligoasthenoteratozoospermic men

“…We could not find any significant association between the methylation of XRCC1 and SDF in our study population (p = .93). Xrcc1 was also suggested to be pivotal for spermatogenesis and Xrcc1 deficiency in primordial germ cells from mice gave rise to impaired spermatogenesis culminating male infertility (C. Xu et al, 2019) and our result that XRCC1 methylation is negatively associated with sperm concentration and normal morphology is in accordance with that. Moreover, XRCC1 has been proposed to have a function in the chromatin remodelling process during spermatid elongation (Zheng et al, 2012).…”

Counteracting Cisplatin-Induced Testicular Damages by Natural Polyphenol Constituent Honokiol

“…In Vivo experiments indicated that as low as 5 mg/kg B.W., nHNK can effectively reduce DNA oxidation in both testis and elongated spermatozoa, as significant reduction (45% less) of testicular 8-OHdG signal was observed when nHNK was given as a treatment upon cisplatin injury. Earlier publication from Xu et al showed that X-ray repair cross-complementation group 1 ( Xrcc1 ), a key DNA repair gene, plays a vital role in maintaining genomic stability during early stage spermatogenesis [ 45 ]; we showed from RNAseq analysis that cisplatin and HNK also altered Xrcc1 gene expression (cisplatin down regulated Xrcc1 gene expression by 3.98 fold when compared with control animal and nHNK upregulated Xrcc1 gene expression by 3.77 fold, data not showed). This finding likely contributed to the observed defect or restoration of DNA breaks and subsequent affects spermatogenesis.…”

Does single-strand DNA break repair capacity influence oocyte maintenance and quality?

“…Similar to PARP, XRCC1 deficiency leads to impaired spermatogenesis and male infertility. Indeed Xrcc1−/− mice exhibited smaller-sized testes, low sperm count, and reduced motility (Xu et al 2019). Furthermore, recent findings demonstrate the importance of XRCC1 during zygotic reprogramming after fertilization.…”