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.

Uterine corpus endometrial carcinoma (UCEC) is a significant cause of cancer-related mortality among women worldwide. Prior research has demonstrated an association between cyclin-dependent kinase inhibitor 2 A (CDKN2A) and various tumors. As a member of the INK4 family, CDKN2A is involved in cell cycle regulation by controlling CDKs. In the present study, bioinformatics was used to analyze public datasets. The expression levels, signaling pathways, and copy number variations of CDKN2A in UCEC were explored, along with its immune cell subset associations. CDKN2A expression was found to be elevated in UCEC, particularly in the signaling pathways involved in cell proliferation and inflammation. Analysis of somatic copy number alterations in the TCGA (The Cancer Genome Atlas)-UCEC dataset revealed a connection between CDKN2A and drug metabolism in UCEC. Assessment of the relationship between CDKN2A and genes involved in immunotherapy for UCEC patients showed a negative correlation between CDKN2A and CD8⁺ T cell activity, as well as IL-2 and TP53. Collectively, these insights suggest that CDKN2A may be a potential biomarker for prognosis and treatment strategies in UCEC.

Centromere localization of the chromosome passenger complex (CPC) is paramount for achieving accurate sister chromosome segregation in mitosis. Although it has been widely recognized that the recruitment of CPC is directly regulated by two histone codes, phosphorylation of histone H3 at threonine 3 (H3T3ph) and phosphorylation of histone H2A at threonine 120 (H2AT120ph), the regulation of CPC localization by other histone codes remains elusive. We show that dysfunction of disruptor of telomeric silencing 1 like (DOT1L) leads to mislocation of the CPC in prometaphase, caused by disturbing the level of H3T3ph and its reader Survivin. This cascade is initiated by over-dephosphorylation of H3T3ph mediated by the phosphatase RepoMan-PP1, whose scaffold RepoMan translocalizes to chromosomes, while the level of H3K79me2/3 is diminished. Together, our findings uncover a biological function of DOT1L and H3K79 methylation in mitosis and give insight into how genomic stability is coordinated by different histone codes.