R-loop-dependent promoter-proximal termination ensures genome stability

Congling Xu, Chengyu Li, Jiwei Chen, Yan Xiong, Zhibin Qiao, Pengyu Fan, Conghui Li, Shuangyu Ma, Jin Liu, Aixia Song, Bolin Tao, Tao Xu, Wei Xu, Yayun Chi, Jingyan Xue, Pu Wang, Dan Ye, Hongzhou Gu, Peng Zhang, Qiong Wang, Ruijing Xiao, Jingdong Cheng, Hai Zheng, Xiaoli Yu, Zhen Zhang, Jiong Wu, Kaiwei Liang, Yan-Jun Liu, Huasong Lu () and Fei Xavier Chen ()
Additional contact information
Congling Xu: Fudan University
Chengyu Li: Zhejiang University
Jiwei Chen: Fudan University
Yan Xiong: Fudan University
Zhibin Qiao: Fudan University
Pengyu Fan: Fudan University
Conghui Li: Wuhan University
Shuangyu Ma: Shanghai Jiao Tong University School of Medicine
Jin Liu: Fudan University
Aixia Song: Fudan University
Bolin Tao: Fudan University
Tao Xu: Anhui Medical University
Wei Xu: Second Military Medical University
Yayun Chi: Fudan University Shanghai Cancer Center
Jingyan Xue: Fudan University Shanghai Cancer Center
Pu Wang: Shanghai Medical College of Fudan University
Dan Ye: Shanghai Medical College of Fudan University
Hongzhou Gu: Fudan University
Peng Zhang: Tongji University School of Medicine
Qiong Wang: Shanghai Jiao Tong University School of Medicine
Ruijing Xiao: Wuhan University
Jingdong Cheng: Fudan University
Hai Zheng: Fudan University
Xiaoli Yu: Fudan University Shanghai Cancer Center, Fudan University
Zhen Zhang: Fudan University Shanghai Cancer Center, Fudan University
Jiong Wu: Fudan University Shanghai Cancer Center
Kaiwei Liang: Wuhan University
Yan-Jun Liu: Fudan University
Huasong Lu: Zhejiang University
Fei Xavier Chen: Fudan University

Nature, 2023, vol. 621, issue 7979, 610-619

Abstract: Abstract The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions1,2. Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS)3 and the transcription regulator Integrator-PP2A (INTAC)4–6. Through SSB1-mediated recognition of single-stranded DNA, SOSS–INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS–INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS–INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation and ensure genome stability.

Date: 2023
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DOI: 10.1038/s41586-023-06515-5

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