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

Author:

Li Ren-Yan1ORCID,Yang Dan2,He Yan-Ji2,Zhou Yong2,Li Cheng-Cheng2,Li Lian-Bing1,Liao Ming-Xing1,Deng Zhong-Liang2,Zhao Le-Tian1,Zhang Tian-Feng1,Luo Yong3,Wang Ying-Xiong4,Gao Yan-Fei5

Affiliation:

1. NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute , Chongqing  401120, China

2. The Second Affiliated Hospital, Chongqing Medical University , Chongqing  400016, China

3. The first Affiliated Hospital, Chongqing Medical University , Chongqing  400016, China

4. Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University , Chongqing  400016, China

5. School of Basic Medical Sciences, Chongqing Medical University , Chongqing  400016, China

Abstract

Abstract 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.

Funder

National Natural Science Foundation of China

Chongqing Municipal Science and Technology Commission Fundamental Research

China Postdoctoral Science Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics

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