RAP80 suppresses the vulnerability of R-loops during DNA double-strand break repair

Takaaki Yasuhara; Reona Kato; Motohiro Yamauchi; Yuki Uchihara; Lee Zou; Kiyoshi Miyagawa; Atsushi Shibata

doi:10.1016/j.celrep.2022.110335

RAP80 suppresses the vulnerability of R-loops during DNA double-strand break repair

Cell Rep. 2022 Feb 1;38(5):110335. doi: 10.1016/j.celrep.2022.110335.

Authors

Takaaki Yasuhara¹, Reona Kato², Motohiro Yamauchi³, Yuki Uchihara⁴, Lee Zou⁵, Kiyoshi Miyagawa⁶, Atsushi Shibata⁷

Affiliations

¹ Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA. Electronic address: tyasuhara-tky@umin.ac.jp.
² Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
³ Hospital Campus Laboratory, Radioisotope Center, Central Institute of Radioisotope Science and Safety Management, Kyushu University, Fukuoka, Japan.
⁴ Gunma University Initiative for Advanced Research, Gunma University, Maebashi, Gunma, Japan.
⁵ Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Electronic address: miyag-tky@umin.ac.jp.
⁷ Gunma University Initiative for Advanced Research, Gunma University, Maebashi, Gunma, Japan. Electronic address: shibata.at@gunma-u.ac.jp.

PMID: 35108530
DOI: 10.1016/j.celrep.2022.110335

Abstract

Single-stranded DNA (ssDNA) arising as an intermediate of cellular processes on DNA is a potential vulnerability of the genome unless it is appropriately protected. Recent evidence suggests that R-loops, consisting of ssDNA and DNA-RNA hybrids, can form in the proximity of DNA double-strand breaks (DSBs) within transcriptionally active regions. However, how the vulnerability of ssDNA in R-loops is overcome during DSB repair remains unclear. Here, we identify RAP80 as a factor suppressing the vulnerability of ssDNA in R-loops, chromosome translocations, and deletions during DSB repair. Mechanistically, RAP80 prevents unscheduled nucleolytic processing of ssDNA in R-loops by CtIP. This mechanism promotes efficient DSB repair via transcription-associated end joining dependent on BRCA1, Polθ, and LIG1/3. Thus, RAP80 suppresses the vulnerability of R-loops during DSB repair, thereby precluding genomic abnormalities in a critical component of the genome caused by deleterious R-loop processing.

Keywords: Double-strand break; R-loop; RAP80; Transcription-associated DSB repair.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA / genetics
DNA Breaks, Double-Stranded / drug effects
DNA End-Joining Repair / physiology
DNA Repair / physiology*
DNA, Single-Stranded / metabolism
DNA-Binding Proteins / metabolism*
Histone Chaperones / metabolism*
Humans
R-Loop Structures / physiology*
RNA / genetics

Substances

DNA, Single-Stranded
DNA-Binding Proteins
Histone Chaperones
UIMC1 protein, human
RNA
DNA