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Poly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage
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Poly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage
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Journal Article
Poly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage
2022
Overview
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.
Fu, et al. report that PARP1-dependent poly(ADP-ribsoyl)ation of the P-TEFb subunit CycT1 suppresses its phase separation, which prevents its interaction partner CDK9 from hyperphosphorylating RNA polymerase II and thereby blocks transcription.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 14/19
/ 14/63
/ 38
/ 38/23
/ 38/39
/ 38/91
/ 42
/ 42/34
/ 82/80
/ 82/83
/ Biomedical and Life Sciences
/ Damage
/ DNA
/ Positive Transcriptional Elongation Factor B - metabolism
/ Repair
/ Ribose
/ RNA
/ RNA Polymerase II - genetics
