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Molecular and Cellular Biology, Genetics

Abstract 2757: Mcl-1 dictates DNA double-strand break repair pathway choice

Guo Chen, Ke Xu, Maohua Xie, Taofeek K. Owonikoko, Suresh S. Ramalingam, Paul W. Doetsch and Xingming Deng
Guo Chen
Emory University, Atlanta, GA.
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Ke Xu
Emory University, Atlanta, GA.
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Maohua Xie
Emory University, Atlanta, GA.
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Taofeek K. Owonikoko
Emory University, Atlanta, GA.
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Suresh S. Ramalingam
Emory University, Atlanta, GA.
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Paul W. Doetsch
Emory University, Atlanta, GA.
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Xingming Deng
Emory University, Atlanta, GA.
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DOI: 10.1158/1538-7445.AM2016-2757 Published July 2016
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Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA

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.

  • ©2016 American Association for Cancer Research.
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Cancer Research: 76 (14 Supplement)
July 2016
Volume 76, Issue 14 Supplement
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Abstract 2757: Mcl-1 dictates DNA double-strand break repair pathway choice
Guo Chen, Ke Xu, Maohua Xie, Taofeek K. Owonikoko, Suresh S. Ramalingam, Paul W. Doetsch and Xingming Deng
Cancer Res July 15 2016 (76) (14 Supplement) 2757; DOI: 10.1158/1538-7445.AM2016-2757

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Abstract 2757: Mcl-1 dictates DNA double-strand break repair pathway choice
Guo Chen, Ke Xu, Maohua Xie, Taofeek K. Owonikoko, Suresh S. Ramalingam, Paul W. Doetsch and Xingming Deng
Cancer Res July 15 2016 (76) (14 Supplement) 2757; DOI: 10.1158/1538-7445.AM2016-2757
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