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; Fei Xavier Chen

doi:10.1038/s41586-023-06515-5

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

Nature. 2023 Sep;621(7979):610-619. doi: 10.1038/s41586-023-06515-5. Epub 2023 Aug 9.

Authors

Congling Xu^#¹, Chengyu Li^#², Jiwei Chen^#¹, Yan Xiong^#¹, Zhibin Qiao^{1

3}, Pengyu Fan^{1

4}, Conghui Li⁵, Shuangyu Ma⁶, Jin Liu¹, Aixia Song¹, Bolin Tao¹, Tao Xu⁷, Wei Xu⁸, Yayun Chi⁹, Jingyan Xue⁹, Pu Wang¹⁰, Dan Ye¹⁰, Hongzhou Gu¹, Peng Zhang⁴, Qiong Wang⁶, Ruijing Xiao⁵, Jingdong Cheng¹, Hai Zheng¹, Xiaoli Yu³, Zhen Zhang³, Jiong Wu⁹, Kaiwei Liang⁵, Yan-Jun Liu¹, Huasong Lu¹¹, Fei Xavier Chen^{12

13}

Affiliations

¹ Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Human Phenome Institute, Fudan University, Shanghai, China.
² Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
³ Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
⁴ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁵ Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
⁶ Department of Histoembryology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.
⁸ Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
⁹ Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
¹⁰ Huashan Hospital, Fudan University, Shanghai Key Laboratory of Medical Epigenetics, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
¹¹ Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China. huasong_lu@zju.edu.cn.
¹² Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Human Phenome Institute, Fudan University, Shanghai, China. feixchen@fudan.edu.cn.
¹³ Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. feixchen@fudan.edu.cn.

^# Contributed equally.

Abstract

The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions^1,2. 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.

MeSH terms

DNA, Single-Stranded / metabolism
DNA-Binding Proteins / metabolism
Genome, Human
Genomic Instability* / genetics
Humans
Mutation
Promoter Regions, Genetic* / genetics
R-Loop Structures* / genetics
RNA Polymerase II / metabolism
Transcription Termination, Genetic*

Substances

DNA, Single-Stranded
RNA Polymerase II
DNA-Binding Proteins