Abstract
Abstract DNA double-strand breaks (DSBs) are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways. The choice of pathway is a critical aspect of DSB repair that is poorly understood. We show that Mcl-1 acts as a functional switch in pathway choice between HR and NHEJ. Mcl-1 is cell cycle-regulated, with expression peaking in S/G2 phase via reduction of its ubiquitination when HR occurs. Mcl-1 depletion reduces HR and enhances NHEJ. Mcl-1 overexpression results in a net increase in HR over NHEJ. Mcl-1 promotes HR-dependent DSB repair following DNA replication stress, which contributes to maintenance of genomic integrity. Mcl-1 directly interacts with Ku via its BH1 and BH3 domains. This interaction is required for Mcl-1 to inhibit Ku-mediated NHEJ, and promote Mre11 complex-mediated DNA resection and HR-dependent DSB repair. Thus, Mcl-1, in addition to its antiapoptotic function, plays an unexpected role in directing DSB repair pathway choice by skewing the balance toward HR during cell cycle progression. Citation Format: Guo Chen, Ke Xu, Maohua Xie, Taofeek K. Owonikoko, Suresh S. Ramalingam, Paul W. Doetsch, Xingming Deng. Mcl-1 dictates DNA double-strand break repair pathway choice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2757.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
