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The multifaceted roles of PARP1 in DNA repair and chromatin remodelling

Key Points

  • Poly(ADP-ribose) polymerase 1 (PARP1) was the first member of the PARP family to be identified. The PARP family now comprises 18 members.

  • PARP1 post-translationally modifies itself and a range of other proteins that have diverse roles in different cellular processes.

  • The catalytic activity of PARP1 is responsible for mediating multiple DNA damage repair pathways.

  • PARP1 has a crucial role in the stabilization of DNA replication forks.

  • The role of PARP1 in remodelling chromatin overlaps with its role in DNA repair.

  • PARP1 inhibition is an attractive strategy for the treatment of cancers that are deficient in the repair of DNA double-strand breaks by homologous recombination.

Abstract

Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers. Understanding the role of PARP1 in maintaining genome integrity is not only important for the design of novel chemotherapeutic agents, but is also crucial for gaining insights into the mechanisms of chemoresistance in cancer cells. In this Review, we discuss the roles of PARP1 in mediating various aspects of DNA metabolism, such as single-strand break repair, nucleotide excision repair, double-strand break repair and the stabilization of replication forks, and in modulating chromatin structure.

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Figure 1: The biochemical functions of poly(ADP-ribose) polymerase 1 in DNA damage repair.
Figure 2: The roles of poly(ADP-ribose) polymerase 1 in excision repair.
Figure 3: The roles of poly(ADP-ribose) polymerase 1 in detection and repair of DNA double-strand breaks.
Figure 4: Poly(ADP-ribose) polymerase 1 helps maintain the stability of replication forks.
Figure 5: Chromatin changes induced by poly(ADP- ribose) polymerase 1 — integrating DNA repair.

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Acknowledgements

The authors are especially grateful to A. Tubbs, S. John and G. Poirier for comments on the manuscript and also for discussions. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), the US National Cancer Institute and the Center for Cancer Research. A.N. was also supported by the US Department of Defense (BCRP DOD Idea Expansion Award BC133858 and BCRP Breakthrough Award BC151331), the Ellison Foundation Award for Aging Research and Alex's Lemonade Stand Foundation Reach Award. A.R.C. has been supported by a Human Frontier Science Program Long-term Fellowship (LT000393/2013).

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Glossary

DNA damage response

(DDR). The collection of cellular pathways that detect, signal and repair DNA damage.

BRCT domain

(BRCA1 C terminus domain). An evolutionarily conserved protein domain that has DNA repair functions; it contains phosphoprotein-binding sites.

Abasic sites

DNA sites that lack either a purine or a pyrimidine base owing to endogenous and/or exogenous DNA damage.

Epistasis

A genetic interaction in which a mutation in one gene masks the effects of a mutation in another gene.

Oxidative base damage

Damage to DNA bases caused by oxidation, which mostly modifies guanine to produce 8-hydroxyguanine.

Alkylation damage

DNA damage mediated by transfer of a single methyl group to a DNA base (mostly to N or O atoms of guanine), which results in the formation of a methyl adduct on the base.

Lesion verification

Verification of a chemical modification on the DNA by the transcription and repair factor transcription factor IIH (TFIIH) during nucleotide excision repair.

Class-switch recombination

(CSR). A process in B cells that involves switching the type of antibody that is produced by changing the constant region of the antibody heavy chain.

V(D)J recombination

A DNA recombination process that occurs during B cell or T cell activation, in which the variable domain exons of antigen receptors are assembled from sub-exonic segments called V, D and J to ultimately generate an immunoglobulin gene or T cell receptor, respectively.

One-ended DSBs

(One-ended DNA double-strand breaks). DSBs formed during collision of ongoing replications forks with a lesion on one strand of the template DNA.

Shelterin complex

A complex of six proteins that binds to TTAGGG repeats at telomeres and protects them from recognition as DNA double-strand breaks.

Terminal transferase

An enzyme that catalyses the addition of nucleotides to 3′ DNA overhangs at double-stranded DNA.

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Ray Chaudhuri, A., Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol 18, 610–621 (2017). https://doi.org/10.1038/nrm.2017.53

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