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

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Huanyi Fu1, Rongdiao Liu2,3, Zixuan Jia1

  • 1Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.

Nature Cell Biology
|April 8, 2022
PubMed

Insights

Poly(ADP-ribose) polymerase 1 (PARP1) halts transcription by inactivating the P-TEFb complex after DNA damage. This process, involving poly(ADP-ribosylation) of cyclin T1, is crucial for DNA repair and cell survival.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • DNA damage triggers a shutdown of transcription to prevent errors and initiate repair.
  • The precise mechanism by which elongating RNA polymerase II (Pol II) is stalled remains incompletely understood.
  • Poly(ADP-ribose) polymerase 1 (PARP1) is a key sensor and initiator of DNA repair pathways.

Purpose of the Study:

  • To elucidate the mechanism by which PARP1 inhibits transcription elongation following DNA damage.
  • To investigate the role of PARP1 in regulating the P-TEFb transcription elongation factor.
  • To understand how PARP1-mediated modifications impact Pol II activity and genomic stability.

Main Methods:

  • Investigated the interaction between activated PARP1 and the P-TEFb complex (CDK9-cyclin T1).
  • Analyzed PARP1-catalyzed poly(ADP-ribosylation) of cyclin T1, focusing on modification sites.
  • Assessed the impact of cyclin T1 modification on its liquid-liquid phase separation and CDK9 activity.
  • Evaluated the functional consequences of P-TEFb inactivation on DNA repair and cell survival.

Main Results:

  • PARP1 directly binds to and inactivates the P-TEFb transcription elongation factor upon sensing DNA damage.
  • PARP1 catalyzes poly(ADP-ribosylation) of cyclin T1, including at rare histidine residues.
  • This modification prevents cyclin T1 liquid-liquid phase separation, inhibiting CDK9-mediated Pol II hyperphosphorylation and elongation.
  • Poly(ADP-ribosylation) of cyclin T1 by PARP1 is essential for efficient DNA repair and cell survival.

Conclusions:

  • PARP1 inhibits Pol II elongation by inactivating P-TEFb through poly(ADP-ribosylation) of cyclin T1.
  • This mechanism represents a critical checkpoint for transcription quality control and genomic integrity.
  • The P-TEFb-PARP1 signaling pathway plays a vital role in cellular response to DNA damage, promoting repair and survival.

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