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Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1210-9. doi: 10.1073/pnas.1418335112. Epub 2015 Mar 2.

BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1.

Author information

1
Department of Cancer and Cell Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267;
2
Institute of Hepatology, Second People's Hospital of Lanzhou, Gansu Province 730046, China;
3
Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030;
4
Department of Surgery, Baylor College of Medicine, Houston, TX 77030; and.
5
Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030; Department of Radiation Oncology, Washington University, St Louis, MO 63108.
6
Department of Cancer and Cell Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267; chunying.du@uc.edu.

Abstract

The DNA damage response (DDR) is crucial for genomic integrity. BRIT1 (breast cancer susceptibility gene C terminus-repeat inhibitor of human telomerase repeat transcriptase expression), a tumor suppressor and early DDR factor, is recruited to DNA double-strand breaks (DSBs) by phosphorylated H2A histone family, member X (γ-H2AX), where it promotes chromatin relaxation by recruiting the switch/sucrose nonfermentable (SWI-SNF) chromatin remodeler to facilitate DDR. However, regulation of BRIT1 recruitment is not fully understood. The baculovirus IAP repeat (BIR)-containing ubiquitin-conjugating enzyme (BRUCE) is an inhibitor of apoptosis protein (IAP). Here, we report a non-IAP function of BRUCE in the regulation of the BRIT1-SWI-SNF DSB-response pathway and genomic stability. We demonstrate that BRIT1 is K63 ubiquitinated in unstimulated cells and that deubiquitination of BRIT1 is a prerequisite for its recruitment to DSB sites by γ-H2AX. We show mechanistically that BRUCE acts as a scaffold, bridging the ubiquitin-specific peptidase 8 (USP8) and BRIT1 in a complex to coordinate USP8-catalyzed deubiquitination of BRIT1. Loss of BRUCE or USP8 impairs BRIT1 deubiquitination, BRIT1 binding with γ-H2AX, the formation of BRIT1 DNA damage foci, and chromatin relaxation. Moreover, BRUCE-depleted cells display reduced homologous recombination repair, and BRUCE-mutant mice exhibit repair defects and genomic instability. These findings identify BRUCE and USP8 as two hitherto uncharacterized critical DDR regulators and uncover a deubiquitination regulation of BRIT1 assembly at damaged chromatin for efficient DDR and genomic stability.

KEYWORDS:

BRIT1; BRUCE; DNA DSB repair; inhibitor of apoptosis

PMID:
25733871
PMCID:
PMC4371995
DOI:
10.1073/pnas.1418335112
[Indexed for MEDLINE]
Free PMC Article

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