ArticleNucleic acids research2023
Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility.
Article in Nucleic acids research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 15 citations in OpenAlex.
- Metal Ion-Mediated Regulation of Cell Fate: A Novel Strategy for Synergy with Radiotherapy and Immunotherapy.Cancers · 2026Review
- Mechanism and potential therapeutic strategies of genetic abnormalities involved in deoxyribonucleic acid double-strand breaks leading to the development of human non-obstructive azoospermia.Reproductive biology and endocrinology : RB&E · 2026Review
- Protective Effect of Lycium Barbarum Polysaccharides and Sodium Selenite on Cadmium Chloride-Induced Testicular Toxicity in Rats.Biological trace element research · 2025Article
- Associations of Serum Per- and Polyfluoroalkyl Substances with Genotoxic Biomarkers: New Insights from Cross-Sectional and In Vivo Evidence.Environmental science & technology · 2025Article
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
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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.
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