MYC Serine 62 phosphorylation promotes its binding to DNA double strand breaks to facilitate repair and cell survival under genotoxic stress.

Abstract

Genomic instability is a hallmark of cancer, driving oncogenic mutations that enhance tumor aggressiveness and drug resistance. MYC, a master transcription factor that is deregulated in nearly all human tumors, paradoxically induces replication stress and associated DNA damage while also increasing expression of DNA repair factors and mediating resistance to DNA-damaging therapies. Emerging evidence supports a non-transcriptional role for MYC in preserving genomic integrity at sites of active transcription and protecting stalled replication forks under stress. Understanding how MYC's genotoxic and genoprotective functions diverge may reveal new therapeutic strategies for MYC-driven cancers. Here, we identify a non-canonical role of MYC in DNA damage response (DDR) through its direct association with DNA breaks. We show that phosphorylation at serine 62 (pS62-MYC) is crucial for the efficient recruitment of MYC to damage sites, its interaction with repair factors BRCA1 and RAD51, and effective DNA repair to support cell survival under stress. Mass spectrometry analysis with MYC-BioID2 during replication stress reveals a shift in MYC's interactome, maintaining DDR associations while losing transcriptional regulators. These findings establish pS62-MYC as a key regulator of genomic stability and a potential therapeutic target in cancers.