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Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility
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 (...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123093/ https://www.ncbi.nlm.nih.gov/pubmed/36869674 http://dx.doi.org/10.1093/nar/gkad128 |
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author | 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 |
author_facet | 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 |
author_sort | Li, Ren-Yan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10123093 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-101230932023-04-25 Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility 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 Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2023-03-03 /pmc/articles/PMC10123093/ /pubmed/36869674 http://dx.doi.org/10.1093/nar/gkad128 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Genome Integrity, Repair and Replication 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 Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility |
title | Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility |
title_full | Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility |
title_fullStr | Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility |
title_full_unstemmed | Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility |
title_short | Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility |
title_sort | heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123093/ https://www.ncbi.nlm.nih.gov/pubmed/36869674 http://dx.doi.org/10.1093/nar/gkad128 |
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