Poly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage

Nat Cell Biol. 2022 Apr;24(4):513-525. doi: 10.1038/s41556-022-00872-5.

Huanyi Fu ^# ¹, Rongdiao Liu ^# ² ³, Zixuan Jia ^# ¹, Ran Li ¹, Feifeng Zhu ², Wenxuan Zhu ¹, Yangqing Shao ¹, Yiyang Jin ³, Yuhua Xue ², Jun Huang ¹ ⁴, Kunxin Luo ³, Xiang Gao ⁵, Huasong Lu ⁶ ⁷, Qiang Zhou ⁸

Affiliations

1 Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
2 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
3 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
4 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.
5 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China. [email protected].
6 Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
7 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. [email protected].
8 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. [email protected].
# Contributed equally.

PMID: 35393539 DOI: 10.1038/s41556-022-00872-5

Abstract

DNA damage shuts down genome-wide transcription to prevent transcriptional mutagenesis and to initiate repair signalling, but the mechanism to stall elongating RNA polymerase II (Pol II) is not fully understood. Central to the DNA damage response, poly(ADP-ribose) polymerase 1 (PARP1) initiates DNA repair by translocating to the lesions where it catalyses protein poly(ADP-ribosylation). Here we report that PARP1 inhibits Pol II elongation by inactivating the transcription elongation factor P-TEFb, a CDK9-cyclin T1 (CycT1) heterodimer. After sensing damage, the activated PARP1 binds to transcriptionally engaged P-TEFb and modifies CycT1 at multiple positions, including histidine residues that are rarely used as an acceptor site. This prevents CycT1 from undergoing liquid-liquid phase separation that is required for CDK9 to hyperphosphorylate Pol II and to stimulate elongation. Functionally, poly(ADP-ribosylation) of CycT1 promotes DNA repair and cell survival. Thus, the P-TEFb-PARP1 signalling plays a protective role in transcription quality control and genomic stability maintenance after DNA damage.

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