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

TitlePoly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage
Authors
Issue Date2022
Citation
Nature Cell Biology, 2022, v. 24, n. 4, p. 513-525 How to Cite?
AbstractDNA 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.
Persistent Identifierhttp://hdl.handle.net/10722/324214
ISSN
2023 Impact Factor: 17.3
2023 SCImago Journal Rankings: 8.913
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFu, Huanyi-
dc.contributor.authorLiu, Rongdiao-
dc.contributor.authorJia, Zixuan-
dc.contributor.authorLi, Ran-
dc.contributor.authorZhu, Feifeng-
dc.contributor.authorZhu, Wenxuan-
dc.contributor.authorShao, Yangqing-
dc.contributor.authorJin, Yiyang-
dc.contributor.authorXue, Yuhua-
dc.contributor.authorHuang, Jun-
dc.contributor.authorLuo, Kunxin-
dc.contributor.authorGao, Xiang-
dc.contributor.authorLu, Huasong-
dc.contributor.authorZhou, Qiang-
dc.date.accessioned2023-01-13T03:02:16Z-
dc.date.available2023-01-13T03:02:16Z-
dc.date.issued2022-
dc.identifier.citationNature Cell Biology, 2022, v. 24, n. 4, p. 513-525-
dc.identifier.issn1465-7392-
dc.identifier.urihttp://hdl.handle.net/10722/324214-
dc.description.abstractDNA 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.-
dc.languageeng-
dc.relation.ispartofNature Cell Biology-
dc.titlePoly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41556-022-00872-5-
dc.identifier.pmid35393539-
dc.identifier.scopuseid_2-s2.0-85127649800-
dc.identifier.volume24-
dc.identifier.issue4-
dc.identifier.spage513-
dc.identifier.epage525-
dc.identifier.eissn1476-4679-
dc.identifier.isiWOS:000779225600001-

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