RT Journal Article
SR Electronic
T1 Abstract 2757: Mcl-1 dictates DNA double-strand break repair pathway choice
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 2757
OP 2757
DO 10.1158/1538-7445.AM2016-2757
VO 76
IS 14 Supplement
A1 Chen, Guo
A1 Xu, Ke
A1 Xie, Maohua
A1 Owonikoko, Taofeek K.
A1 Ramalingam, Suresh S.
A1 Doetsch, Paul W.
A1 Deng, Xingming
YR 2016
UL http://cancerres.aacrjournals.org/content/76/14_Supplement/2757.abstract
AB Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LADNA 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.