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The expanding universe of PARP1-mediated molecular and therapeutic mechanisms

Dan Huang1, W Lee Kraus2

  • 1Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.

Molecular Cell
|March 10, 2022
PubMed

Insights

ADP-ribosylation (ADPRylation) by PARP enzymes, particularly PARP1, extends beyond DNA repair to regulate gene expression, chromatin, and RNA biology. New insights reveal novel regulatory mechanisms and therapeutic strategies for PARP inhibitors, including resistance.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • ADP-ribosylation (ADPRylation) is a protein modification catalyzed by ADP-ribosyl transferase (ART) enzymes, notably nuclear Poly(ADP-ribose) polymerases (PARPs).
  • While historically linked to DNA damage responses in cancer, PARP functions are now recognized in diverse biological processes.
  • PARP1, a key family member, plays a central role in these expanding functions.

Purpose of the Study:

  • To summarize the expanding molecular mechanisms of nuclear PARPs, focusing on PARP1.
  • To review novel regulatory concepts and therapeutic advancements related to PARP1.
  • To discuss progress in understanding and overcoming PARP inhibitor resistance.

Main Methods:

  • Literature review and synthesis of recent research findings.
  • Analysis of molecular mechanisms underlying PARP1 functions.
  • Review of therapeutic strategies and resistance mechanisms for PARP inhibitors.

Main Results:

  • PARP1 is involved in DNA repair, chromatin regulation, gene expression, ribosome biogenesis, and RNA biology.
  • New regulatory concepts include PAR-dependent post-translational modifications, "ADPR spray," and PAR-mediated biomolecular condensate formation.
  • Advances in PARP inhibitor (PARPi) mechanisms and resistance pathways have been identified.

Conclusions:

  • Recent progress has significantly expanded our understanding of PARP1's diverse molecular and therapeutic roles.
  • PARP1's functions extend far beyond DNA repair, impacting multiple cellular processes.
  • New insights into PARPi mechanisms and resistance are crucial for effective cancer therapy.
Keywords:
ADP-ribosylationDNA damage responseDNA replicationPARPPARP inhibitorPARPiPTMRNA biologybiomolecular condensatechromatingene regulationhistonepoly(ADP-ribose) polymerasepost-translational modificationribosome biogenesistherapeutic resistancetherapeutics

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