Abstract LB-263: P53 promotes replication genome stability by epigenetics-enabled MRE11 restart

Abstract

Abstract DNA damage activates p53, the most frequently mutated tumor suppressor, to guard the genome and control gene transcription, epigenetics and apoptosis. Yet, how p53 suppresses genome instability remains ill-defined and is clouded by its genome-wide alterations. Here, enabled by our kPOND technology for single-cell nascent DNA/protein interactions and single-molecule DNA spreading, we define p53’s role in promoting genomic stability by enabling replication restart of stalled replication forks. Mechanistically, p53 enables MRE11 nuclease recruitment for stalled replication fork restart via control of epigenetic factor. We find an apoptosis-proficient and tumor promoting p53 mutant allele to be replication restart defective, while an apoptosis defective and poorly tumor-promoting murine p53 allele remains mostly restart proficient, revealing an improved correlation of restart functions with tumorigenesis compared to apoptosis functions. Importantly, both null and p53 gain-of-function (GOF) mutant cells show restart defects resulting in replication dependent genomic instability, uncovering a common function defect aside gene transcription. Both mutant and p53 null cells show increased recruitment of error-prone repair factors and DNA polymerases, providing a mechanism for genomic instability observed in these cells by pathway homeostasis imbalance. Collective results unveil a common transcription-independent pathway defect for both p53 null and GOF mutants laying groundwork for new targeting strategies of p53 defects in cancer. Note: This abstract was not presented at the meeting. Citation Format: Katharina Schlacher, Sunetra Roy, Karl-Heinz Tomaszowski. P53 promotes replication genome stability by epigenetics-enabled MRE11 restart [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-263. doi:10.1158/1538-7445.AM2017-LB-263