Abstract

Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a transcribed locus in human cells. As canonical HR, TC-HR requires RAD51. However, the localization of RAD51 to damage sites during TC-HR does not require BRCA1 and BRCA2, but relies on RAD52 and Cockayne Syndrome Protein B (CSB). During TC-HR, RAD52 is recruited by CSB through an acidic domain. CSB in turn is recruited by R loops, which are strongly induced by ROS in transcribed regions. Notably, CSB displays a strong affinity for DNA:RNA hybrids in vitro, suggesting that it is a sensor of ROS-induced R loops. Thus, TC-HR is triggered by R loops, initiated by CSB, and carried out by the CSB-RAD52-RAD51 axis, establishing a BRCA1/2-independent alternative HR pathway protecting the transcribed genome.

Details

Title
ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB
Author
Teng, Yaqun 1 ; Yadav, Tribhuwan 2 ; Duan, Meihan 1 ; Tan, Jun 3 ; Xiang, Yufei 4 ; Gao, Boya 3 ; Xu, Jianquan 5 ; Liang, Zhuobin 6 ; Liu, Yang 5   VIAFID ORCID Logo  ; Nakajima, Satoshi 7 ; Shi, Yi 4 ; Levine, Arthur S 7 ; Zou, Lee 8 ; Li, Lan 9 

1  School of Medicine, Tsinghua University, Beijing, China; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA 
2  Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA 
3  UPMC Hillman Cancer Center, Pittsburgh, PA, USA 
4  Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 
5  Department of Medicine and Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA 
6  Department of Molecular Biology and Biophysics, Yale Medical School, New Haven, CT, USA 
7  Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA 
8  Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
9  Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
Pages
1-12
Publication year
2018
Publication date
Oct 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-06586-3
ProQuest document ID
2117206072
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.