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

Autor: Alpana Kumari, George C. Prendergast, Tetsushi Iwasaki, Daitoku Sakamuro, Walson P. Folk, Slovénie Pyndiah, Amy L. Abdulovic-Cui, John M. Sedivy
Rok vydání: 2016
Předmět:
Zdroj: Molecular Cancer Research. 14:PR09-PR09
ISSN: 1557-3125
1541-7786
DOI: 10.1158/1557-3125.cellcycle16-pr09
Popis: During DNA synthesis, single-stranded DNA breaks (SSBs) are easily produced by mitogenic and oxidative stresses. Although SSBs are naturally converted to double-stranded DNA breaks (DSBs) at the collapse of replication forks, the integrity of chromosomal DNA is regularly maintained during DNA synthesis. Because DNA replication is a fundamental biological process involved in homeostasis, we hypothesized that an S-phase-associated guardian of the genome constantly stimulates cellular DSB repair machinery during DNA replication. The p53 tumor suppressor is known to act as the guardian of the genome. However, in response to DSBs, p53 not only activates G1 arrest, but also represses RAD51, a key component of homologous recombination (HR), an error-free DSB repair mechanism. Moreover, p53 is regularly dormant in actively growing cells. Thus, p53 cannot be the S-phase-associated DNA-repair enhancer. In this study, we show that the c-MYC transcription factor, which promotes DNA replication, concomitantly stimulates ataxia telangiectasia mutated kinase (ATM), γH2AX 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 γH2AX), which has been widely used as a biomarker of DSBs. Reduced BIN1-dependent γH2AX 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 γH2AX foci, the oncoprotein has been thought to induce real DSBs. However, c-MYC silencing did not diminish γH2AX foci in the absence of BIN1, suggesting that c-MYC-induced γH2AX 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 γH2AX as a novel warning beacon of imminent DSBs and establishes a new paradigm for c-MYC in facilitating DSB-repair signaling during DNA replication. This abstract is also being presented as Poster B20. Citation Format: Alpana Kumari, Tetsushi Iwasaki, Walson P. Folk, Amy L. Abdulovic-Cui, Slovénie Pyndiah, George C. Prendergast, John M. Sedivy, Daitoku Sakamuro. c-MYC preserves genomic integrity during DNA replication: a paradigm shift of c-MYC. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR09.
Databáze: OpenAIRE
Externí odkaz: