Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility

作者全名："Li, Ren-Yan; Yang, Dan; He, Yan-Ji; Zhou, Yong; Li, Cheng-Cheng; Li, Lian-Bing; Liao, Ming-Xing; Deng, Zhong-Liang; Zhao, Le-Tian; Zhang, Tian-Feng; Luo, Yong; Wang, Ying-Xiong; Gao, Yan-Fei"

作者地址："[Gao, Yan-Fei] Chongqing Med Univ, Sch Basic Med Sci, Chongqing, Peoples R China; [Li, Ren-Yan; Li, Lian-Bing; Liao, Ming-Xing; Zhao, Le-Tian; Zhang, Tian-Feng] Chongqing Populat & Family Planning Sci & Technol, NHC Key Lab Birth Defects & Reprod Hlth, Chongqing, Peoples R China; [Yang, Dan; He, Yan-Ji; Zhou, Yong; Li, Cheng-Cheng; Deng, Zhong-Liang] Chongqing Med Univ, Affiliated Hosp 2, Chongqing, Peoples R China; [Luo, Yong] Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China; [Wang, Ying-Xiong] Chongqing Med Univ, Joint Int Res Lab Reprod & Dev, Chongqing, Peoples R China"

通信作者："Gao, YF (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Chongqing, Peoples R China.; Luo, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China.; Wang, YX (通讯作者)，Chongqing Med Univ, Joint Int Res Lab Reprod & Dev, Chongqing, Peoples R China."

来源：NUCLEIC ACIDS RESEARCH

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000943220300001

JCR分区：Q1

影响因子：16.6

年份：2023

卷号：51

期号：7

开始页：3150

结束页：3165

文献类型：Article

关键词：　

摘要："DNA double-strand breaks (DSBs) are functionally linked to genomic instability in spermatocytes and to male infertility. The heavy metal cadmium (Cd) is known to induce DNA damage in spermatocytes by unknown mechanisms. Here, we showed that Cd ions impaired the canonical non-homologous end-joining (NHEJ) repair pathway, but not the homologous recombination (HR) repair pathway, through stimulation of Ser2056 and Thr2609 phosphorylation of DNA-PKcs at DSB sites. Hyper-phosphorylation of DNA-PKcs led to its premature dissociation from DNA ends and the Ku complex, preventing recruitment of processing enzymes and further ligation of DNA ends. Specifically, this cascade was initiated by the loss of PP5 phosphatase activity, which results from the dissociation of PP5 from its activating ions (Mn), that is antagonized by Cd ions through a competitive mechanism. In accordance, in a mouse model Cd-induced genomic instability and consequential male reproductive dysfunction were effectively reversed by a high dosage of Mn ions. Together, our findings corroborate a protein phosphorylation-mediated genomic instability pathway in spermatocytes that is triggered by exchange of heavy metal ions."

基金机构："National Natural Science Foundation of China [31870768, 32071295]; Chongqing Municipal Science and Technology Commission [cstc2020jxjl0018, cstc2021jcyj-msxmX0304]; China Post-doctoral Science Foundation [2018M643428]"

基金资助正文："National Natural Science Foundation of China [31870768, 32071295]; Chongqing Municipal Science and Technology Commission Fundamental Research funded project [cstc2020jxjl0018, cstc2021jcyj-msxmX0304]; China Post-doctoral Science Foundation [2018M643428].FUNDING for open access charge: National Natural Science Foundation of China [31870768]."