Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy

Drug resistance significantly limits the efficacy of chemotherapy. The DNA mismatch repair (MMR) system maintains genomic stability by correcting DNA errors. During DNA-damaging treatments, cancer cells transiently increase their adaptive mutability, also known as microsatellite instability (MSI), to evade therapeutic pressure through MMR downregulation, conferring drug resistance. However, an understanding of the underlying mechanisms of MMR protein downregulation under DNA-damaging drugs remains limited. Our study reveals a negative correlation between SIRT7 protein levels and MMR core protein MSH2 levels in cervical and lung cancer tissues. SIRT7 destabilizes MSH2, promoting MSI and mutagenesis. Molecularly, DNA damage triggers ATM kinase-dependent phosphorylation and subcellular redistribution of SIRT7. Phosphorylated SIRT7 interacts with and deacetylates MSH2, impairing MMR, and inducing MSI and drug resistance. Our findings suggest that SIRT7 drives MMR downregulation under therapeutic stress and that ATM-dependent phosphorylation of SIRT7 may serve as a predictive biomarker for chemotherapeutic efficacy and a target for cancer treatment.