Abstract PR09: c-MYC preserves genomic integrity during DNA replication: a paradigm shift of c-MYC

In this study, we show that the c-MYC transcription factor, which promotes DNA replication, concomitantly stimulates ataxia telangiectasia mutated kinase (ATM), H2AX formation, and DSB repair by repressing BIN1. As an E2F1 corepressor, BIN1 suppressed the human ATM promoter, whereas via protein-protein interaction, BIN1 negatively regulated ATM auto-phosphorylation at serine 1981, a critical step for ATM activation. Accordingly, even before DSBs were formed, impaired BIN1 was sufficient to enhance ATM-dependent phosphorylation of histone H2AX at serine 139 (forming H2AX), which has been widely used as a biomarker of DSBs. Reduced BIN1-dependent H2AX foci formation was accompanied by the phosphorylation of MDC1 (mediator of DNA damage checkpoint protein 1) and 53BP1 foci. Furthermore, loss of BIN1 substantially accelerated cellular DSB-repair activity, which was reversed by the depletion of BRCA2, a critical player of HR. Intriguingly, activated c-MYC recruited the chromatin-remodeling factor BRG1 to and transcriptionally repressed the BIN1 promoter, thus indirectly liberating ATM expression. Because c-MYC robustly increases H2AX foci, the oncoprotein has been thought to induce real DSBs. However, c-MYC silencing did not diminish H2AX foci in the absence of BIN1, suggesting that c-MYC-induced H2AX foci formation is chiefly attributable to c-MYC-induced decrease in BIN1 and following ATM reactivation in a manner independent of DSBs. Our study identifies c-MYC-associated H2AX as...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research