Open AccessPoly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage
Author(s) -
Huanyi Fu,
Rongdiao Liu,
Zixuan Jia,
Ran Li,
Fengsen Zhu,
Wenxuan Zhu,
Yangqing Shao,
Yiyang Jin,
Yuhua Xue,
Jun Huang,
Kunxin Luo,
Xiang Gao,
Huasong Lu,
Qiang Zhou
Publication year - 2022
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-022-00872-5
Subject(s) - p tefb , dna damage , rna polymerase ii , parp1 , processivity , biology , microbiology and biotechnology , polymerase , elongation factor , transcription (linguistics) , adp ribosylation , dna repair , poly adp ribose polymerase , dna , rna , biochemistry , enzyme , gene expression , gene , promoter , ribosome , linguistics , philosophy , nad+ kinase
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.