CommentaryThe diverse roles and clinical relevance of PARPs in DNA damage repair: Current state of the art☆
Graphical abstract
Introduction
Throughout its biological life, the genome is continuously exposed to a variety of lesions arising from exogenous (UV component of sunligth, genotoxic chemicals, ionizing radiation) or endogenous origins (reactive oxygen species, abasic sites, deamination-induced miscoding bases). To cope with these multiple DNA lesions, eukaryotic cells can activate different important and perfectly coordinated defensive mechanisms involving detection and signaling pathways, chromatin remodeling, DNA repair processes and cell-cycle checkpoints. Among these responses, PARP1 catalyzed poly(ADP-ribosyl)ation appeared rapidly as a critical post-translational modification involved in the detection, signaling as well as organized repair of single and double-strand breaks. The considerable efforts displayed on the biochemical and cellular characterization of poly(ADP-ribosyl)ation in addition to the generation and phenotyping of PARP-loss of function mouse models have considerably improved our understanding of the repair associated nuclear actions of PARPs and have sparked development of novel anti-cancer therapeutic strategies involving PARP inhibition.
In this manuscript, we first propose to briefly review some basic informations about the dynamic nature and the known actions of poly(ADP-ribosyl)ation catalyzed in response to DNA damage with a particular focus on its involvement in chromatin response. In subsequent sections, we provide an overview of the key aspects of PARPs biology in DNA repair pathways, and we highlight the clinical benefits of PARP1 inhibition in cancer therapy.
Section snippets
The biological means of DNA damage-driven synthesis of poly(ADP-ribose) (PAR)
Studies over the last decades have largely contributed to describe PARP1-catalyzed poly(ADP-ribosyl)ation as one of the earliest response to DNA damage that plays pivotal roles in the processing and resolution of the damaged DNA. The widely accepted scheme is that in response to DNA strand interruptions, the initial role of PARP1 is to detect DNA strand breaks and catalyze the transfer of successive units of ADP-ribose moieties using NAD+ as a substrate mostly onto itself in an automodification
The emerging importance of PARP1 in remodeling damaged chromatin
Notably, PARP1 catalyzed poly(ADP-ribosyl)ation contributes to DNA repair in many ways as outlined below. However, perhaps its ability to modulate chromatin structure and function appears as the earliest and major event detectable at sites of DNA strand breaks. Interestingly, the outcome of poly(ADP-ribose) synthesis in terms of chromatin plasticity is dual and somehow paradoxical. A widely accepted assumption is that PARP activity favors chromatin relaxation to facilitate the access of the
The DNA-damage dependent PARPs in DNA repair pathways
In the past decade, bioinformatic and genomic approaches have identified PARP1 as the founding member of a PARP family containing 17 proteins all endowed with a conserved catalytic domain although not all of them catalyze poly(ADP-ribosyl)ation [1]. Within this family, so far only PARP1, PARP2 and more recently PARP3 have been defined as DNA-damage dependent PARPs. Despite high structural similarities within their catalytic domains, the three proteins display significant structural differences
The clinical relevance of PARPs in DNA repair
The recent remarkable and elegant progress in the biological and mechanistic repair functions of PARP1 as outlined above, has placed its inhibition at the forefront of therapeutic strategies following two major schemes: (i) to potentialize the cytotoxic action of ionizing radiation or clastogenic anti-tumoral drugs; (ii) to sensitize HR-recombination deficient human cancers in a synthetic lethality approach.
Conclusion
As we have tried to draw it here, PARP-catalyzed poly(ADP-ribosyl)ation is now recognized as one of the earliest and key driving force in cellular response to DNA damage. PARP acts as a DNA nick sensor and the resulting poly(ADP-ribose) is thought to organize chromatin states and serves as a scaffold for subsequent recruitment of repair proteins at DNA damage sites. This property has open a new chapter in the field aimed to exploit PARP inhibition as a therapeutic opportunity in cancer
References (74)
- et al.
The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets
Mol Cell
(2010) - et al.
DNA repair factor APLF is a histone chaperone
Mol Cell
(2011) - et al.
PARP-3 and APLF function together to accelerate nonhomologous end-joining
Mol Cell
(2011) - et al.
Toward specific functions of poly(ADP-ribose) polymerase-2
Trends Mol Med
(2008) - et al.
The DNA damage response: making it safe to play with knives
Mol Cell
(2010) - et al.
Human proliferating cell nuclear antigen, poly(ADP-ribose) polymerase-1, and p21waf1/cip1. A dynamic exchange of partners
J Biol Chem
(2003) - et al.
Condensin I interacts with the PARP-1-XRCC1 complex and functions in DNA single-strand break repair
Mol Cell
(2006) - et al.
Photoaffinity labeling of mouse fibroblast enzymes by a base excision repair intermediate. Evidence for the role of poly(ADP-ribose) polymerase-1 in DNA repair
J Biol Chem
(2001) - et al.
DNA polymerase beta-mediated long patch base excision repair. Poly(ADP-ribose)polymerase-1 stimulates strand displacement DNA synthesis
J Biol Chem
(2001) - et al.
ATP for the DNA ligation step in base excision repair is generated from poly(ADP-ribose)
J Biol Chem
(2000)
Poly(ADP-ribose) polymerase and Ku autoantigen form a complex and synergistically bind to matrix attachment sequences
J Biol Chem
PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites
J Biol Chem
Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents
J Biol Chem
Lethality in PARP-1/Ku80 double mutant mice reveals physiological synergy during early embryogenesis
DNA Repair
ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin
Mol Cell
Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining
J Biol Chem
Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) polymerase
J Biol Chem
PARP-3 is a mono-ADP-ribosylase that activates PARP-1 in the absence of DNA
J Biol Chem
Tankyrase promotes telomere elongation in human cells
Curr Biol
The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings
Mol Oncol
A snapshot of chemoresistance to PARP inhibitors
Trends Pharmacol Sci
Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins
J Biol Chem
The expanding field of poly(ADP-ribosyl)ation reactions.‘protein modifications: beyond the usual suspects’ review series
EMBO Rep
Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors
Nat Rev Drug Discov
Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler
Proc Natl Acad Sci U S A
Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair
Genes Dev
A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation
Nat Struct Mol Biol
A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage
Proc Natl Acad Sci U S A
Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4
EMBO J
Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression
Proc Natl Acad Sci U S A
Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells
Proc Natl Acad Sci U S A
DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines
Nucleic Acids Res
Base excision repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1
Biochemistry
Poly(ADP-ribose) polymerase 1 (PARP-1) binds to 8-oxoguanine-DNA glycosylase (OGG1)
J Biol Chem
Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage
Hum Mol Genet
Passing the baton in base excision repair
Nat Struct Biol
Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells
Nucleic Acids Res
Cited by (0)
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We would like to apologize for uncited work due to limitations by the journal format. MDV is a recipient of a Fonds National de la Recherche-Luxembourg PhD fellowship. This work was supported by grants from Association pour la Recherche sur le Cancer, Ligue Nationale et Régionale Contre le Cancer, Agence Nationale pour la Recherche, Centre National de la Recherche Scientifique et Université de Strasbourg.