ZMYM3 S464：エピジェネティックリモデリングおよび発がんにおける潜在的なリン酸化調節ハブ

Dysregulated epigenetic control and DNA-repair defects are hallmarks of many cancers and neurodevelopmental disorders. ZMYM3, a chromatin-associated zinc-finger protein, orchestrates histone deacetylation, BRCA1-dependent homologous recombination (HR), and cytoskeletal organisation, yet the post-translational mechanisms that govern its activity remain largely unknown. Here we integrate global phosphoproteomics data to define the regulatory landscape of ZMYM3, with a focus on the highly recurrent phosphosite S464 located in its zinc-finger domain. S464 is detected in > 50% of curated human-cell-line datasets and is co-regulated with four upstream kinases (CDK13, HIPK1, CDK9, CLK3) and 15 binary interactors including BRCA1, HDAC6, and SWI/SNF components. Positively co-phosphorylated networks are enriched for chromatin remodelling, mitotic segregation, DNA-damage response, and cytoskeletal dynamics. cProSite analysis of patient tumours reveals striking S464 hyper-phosphorylation in breast and ovarian cancers, correlating with HR-deficiency signatures. ZMYM3 S464 emerges as a phospho-regulatory hub that coordinates epigenetic silencing, HR repair, and mitotic fidelity. Its cancer-type-specific upregulation offers a novel biomarker for HR-deficiency stratification and a therapeutic entry point for modulating BRCA1 function or epigenetic drug sensitivity; functional validation in HR-deficient models is now warranted.