ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB

Yaqun Teng, Tribhuwan Yadav, Meihan Duan, Jun Tan, Yufei Xiang, Boya Gao, Jianquan Xu, Zhuobin Liang, Yang Liu, Satoshi Nakajima, Yi Shi, Arthur S. Levine, Lee Zou and Li Lan ()
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Yaqun Teng: Tsinghua University
Tribhuwan Yadav: Harvard Medical School
Meihan Duan: Tsinghua University
Jun Tan: UPMC Hillman Cancer Center
Yufei Xiang: University of Pittsburgh School of Medicine
Boya Gao: UPMC Hillman Cancer Center
Jianquan Xu: University of Pittsburgh
Zhuobin Liang: Yale Medical School
Yang Liu: University of Pittsburgh
Satoshi Nakajima: University of Pittsburgh School of Medicine
Yi Shi: University of Pittsburgh School of Medicine
Arthur S. Levine: University of Pittsburgh School of Medicine
Lee Zou: Harvard Medical School
Li Lan: University of Pittsburgh School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06586-3

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