GRB2 Enforces Homology-Directed Repair Initiation by MRE11

Authors

Zu Ye, University of Texas MD Anderson Cancer Center
Shengfeng Xu, University of Texas MD Anderson Cancer Center
Yin Shi, Zhejiang University School of Medicine
Albino Bacolla, University of Texas MD Anderson Cancer Center
Aleem Syed, University of Texas MD Anderson Cancer Center
Davide Moiani, University of Texas MD Anderson Cancer Center
Chi Lin Tsai, University of Texas MD Anderson Cancer Center
Qiang Shen, LSU Health Sciences Center- New OrleansFollow
Guang Peng, University of Texas MD Anderson Cancer Center
Paul G. Leonard, University of Texas MD Anderson Cancer Center
Darin E. Jones, University of Arkansas for Medical Sciences
Bin Wang, University of Texas MD Anderson Cancer Center
John A. Tainer, University of Texas MD Anderson Cancer Center
Zamal Ahmed, University of Texas MD Anderson Cancer Center

Document Type

Article

Publication Date

8-1-2021

Publication Title

Science Advances

Abstract

DNA double-strand break (DSB) repair is initiated by MRE11 nuclease for both homology-directed repair (HDR) and alternative end joining (Alt-EJ). Here, we found that GRB2, crucial to timely proliferative RAS/MAPK pathway activation, unexpectedly forms a biophysically validated GRB2-MRE11 (GM) complex for efficient HDR initiation. GRB2-SH2 domain targets the GM complex to phosphorylated H2AX at DSBs. GRB2 K109 ubiquitination by E3 ubiquitin ligase RBBP6 releases MRE11 promoting HDR. RBBP6 depletion results in prolonged GM complex and HDR defects. GRB2 knockout increased MRE11-XRCC1 complex and Alt-EJ. Reconstitution with separation-of-function GRB2 mutant caused HDR deficiency and synthetic lethality with PARP inhibitor. Cell and cancer genome analyses suggest biomarkers of low GRB2 for noncanonical HDR deficiency and high MRE11 and GRB2 expression for worse survival in HDR-proficient patients. These findings establish GRB2’s role in binding, targeting, and releasing MRE11 to promote efficient HDR over Alt-EJ DSB repair, with implications for genome stability and cancer biology.

First Page

1

Last Page

18

PubMed ID

34348893

Volume

7

Issue

32

Publisher

American Association for the Advancement of Science

Recommended Citation

Ye, Zu; Xu, Shengfeng; Shi, Yin; Bacolla, Albino; Syed, Aleem; Moiani, Davide; Tsai, Chi Lin; Shen, Qiang; Peng, Guang; Leonard, Paul G.; Jones, Darin E.; Wang, Bin; Tainer, John A.; and Ahmed, Zamal, "GRB2 Enforces Homology-Directed Repair Initiation by MRE11" (2021). School of Medicine Faculty Publications. 58.
https://digitalscholar.lsuhsc.edu/som_facpubs/58
10.1126/sciadv.abe9254