@article{6392eaaea2d94b51bd27e0bdbe54707b,
title = "Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity",
abstract = "Bromodomain proteins (BRD) are key chromatin regulators of genome function and stability as well as therapeutic targets in cancer. Here, we systematically delineate the contribution of human BRD proteins for genome stability and DNA double-strand break (DSB) repair using several cell-based assays and proteomic interaction network analysis. Applying these approaches, we identify 24 of the 42 BRD proteins as promoters of DNA repair and/or genome integrity. We identified a BRD-reader function of PCAF that bound TIP60-mediated histone acetylations at DSBs to recruit a DUB complex to deubiquitylate histone H2BK120, to allowing direct acetylation by PCAF, and repair of DSBs by homologous recombination. We also discovered the bromo-and-extra-terminal (BET) BRD proteins, BRD2 and BRD4, as negative regulators of transcription-associated RNA-DNA hybrids (R-loops) as inhibition of BRD2 or BRD4 increased R-loop formation, which generated DSBs. These breaks were reliant on topoisomerase II, and BRD2 directly bound and activated topoisomerase I, a known restrainer of R-loops. Thus, comprehensive interactome and functional profiling of BRDproteins revealed new homologous recombination and genome stability pathways, providing a framework to understand genome maintenance by BRD proteins and the effects of their pharmacological inhibition.",
keywords = "DNA damage response, DNA repair, R-loops, bromodomain, chromatin, homologous recombination",
author = "Kim, {Jae Jin} and Lee, {Seo Yun} and Fade Gong and Battenhouse, {Anna M.} and Boutz, {Daniel R.} and Aarti Bashyal and Refvik, {Samantha T.} and Chiang, {Cheng Ming} and Blerta Xhemalce and Paull, {Tanya T.} and Brodbelt, {Jennifer S.} and Marcotte, {Edward M.} and Miller, {Kyle M.}",
note = "Funding Information: We thank members of the Miller laboratory for their discussions of this study and critical reading of the manuscript. This work in the K.M.M. laboratory was supported in part through grants from the National Cancer Institute, National Institutes of Health (NIH, CA198279 and CA201268), and the American Cancer Society (RSG-16-042-01). C-M.C. is supported by grants RP180349 and RP190077 from the Cancer Prevention & Research Institute of Texas (CPRIT). B.X. acknowledges support from NIH grant R01 GM127802. J.S.B. acknowledges support from the National Science Foundation (CHE-1402753) and the Robert A. Welch Foundation (F-1155). Funding from the UT System for support of the UT System Proteomics Core Facility Network is gratefully acknowledged. E.M.M. acknowledges support from the Welch Foundation (F-1515), NIH (R35 GM122480), and Army Research Laboratory Cooperative Agreement number W911NF-17-2-0091. Part of the research in the E.M.M. laboratory was sponsored by the Army Research Laboratory and was accomplished under Cooperative Agreement number W911NF-17-2-0091. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Army Research Laboratory or the US Government. The US Government is authorized to reproduce and distribute reprints for government purposes notwithstanding any copyright notation herein. Publisher Copyright: {\textcopyright} 2019 Kim et al.",
year = "2019",
month = dec,
day = "1",
doi = "10.1101/gad.331231.119",
language = "English (US)",
volume = "33",
pages = "1751--1774",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "23-24",
}