ReviewFunctional aspects of PARylation in induced and programmed DNA repair processes: Preserving genome integrity and modulating physiological events
Introduction
The chemical stability of the genome is permanently challenged by both intracellular (byproducts of normal metabolism) and extracellular toxic stresses (ionizing radiations, chemical agents). If not repaired or incorrectly repaired, the lesions can result in mutations and chromosomal aberrations, diseases and cell death (Friedberg et al., 2006, Hoeijmakers, 2001a, Hoeijmakers, 2001b, Jackson and Bartek, 2009). To protect their genome against the deleterious consequences of these lesions, mammalian organisms have developed sophisticated cellular networks to detect the DNA damage, signal its presence and stimulate the appropriate repair pathway (Ciccia and Elledge, 2010).
In the last decade, several reports have highlighted the major contribution of post-translational modifications such as phosphorylation, sumoylation and acetylation in controlling these three events (Polo and Jackson, 2011). Recently, PARylation has emerged as an additional key regulator as highlighted throughout this review.
PARylation is the process whereby a linear or multibranched polymer of ADP-ribose units (termed PAR for poly(ADP-ribose)) that is catalyzed by Poly(ADP-ribose) polymerases (PARPs) is covalently attached to Glu, Lys or Asp residues of acceptor proteins (heteromodification) or onto PARP itself (automodification) (Hakme et al., 2008, Hottiger et al., 2010, Krishnakumar and Kraus, 2010). Among the 17 members of the PARP family, so far only PARP1, PARP2 and PARP3 have been found to be induced by DNA strand breaks and characterized for their role in cellular response to DNA damage (reviewed in (De Vos et al., 2012)). Although it requires further investigation, it seems likely from recent studies that the telomere associated PARP Tankyrase 1 (PARP5) also plays an important role in genome maintenance (De Vos et al., 2012, Dregalla et al., 2010, White et al., 2009).
The extent of the PARylation response to DNA damage largely depends on the nature and amount of DNA breaks produced. In response to low levels of DNA lesions, PARP activity favors repair and survival. In the presence of extensive DNA injury as observed during ischemia/reperfusion and inflammatory conditions, the massive production of PAR ultimately causes cell-death via at least two distinct mechanisms: energy-failure induced necrosis or apoptosis-inducing factor (AIF) dependent apoptosis (Luo and Kraus, 2012). A tight regulation of PARylation homeostasis is therefore of critical importance for efficient repair when cells are exposed to sub-lethal doses of DNA damage. As such, the transient and highly dynamic nature of PAR is regulated by its rapid reversal by the activity of the poly(ADP-ribose) glycohydrolase PARG and presumably also the ADP-ribosylarginine hydrolase ARH3 (Davidovic et al., 2001, Oka et al., 2006).
Determination of the structural properties of PARP1, PARP2, PARP3 and PARG together with the phenotyping of the gene knockout animals have been instrumental in revealing the key functions of these proteins in response to genotoxic stress (reviewed in (Hottiger et al., 2010, Krishnakumar and Kraus, 2010, Schreiber et al., 2006, Yelamos et al., 2008)) (Table 1).
PAR is now recognized as a central post-translational protein modification that coordinates the building of repair complexes at damage sites with the timely controlled dissociation of the repair factors. Furthermore, through its multiple functions in response to DNA damage, the PAR synthesized by PARP1 and PARP2 also operates in diverse biological events induced by programmed DNA breakage either to generate immune-receptor diversity or healthy gametes for sexual reproduction and likely also to facilitate viral integration.
In this review, we develop the above mentioned properties of PARylation in stress conditions. More particularly, we describe how the DNA-damage induced PARylation and its homeostasis regulate the diverse repair events, and we highlight the biological significance of this response particularly to programmed DNA strand breaks produced during physiological processes. Special emphasis is given to the participation of PARylation in the mechanisms driving the assembly and the diversification of the antibody repertoire.
Section snippets
PAR acts as a landing platform for the focal assembly of repair proteins
One hallmark of PAR synthesis in response to DNA damage is the formation of a large number of discrete foci in the nucleus of the treated cells that can be easily detected using a fluorescent labeled anti-PAR antibody by normal immunofluorescence. However, only few studies have been able to colocalize these PAR foci with the assembly of repair factors at DNA damaged sites or stalled replication forks (Bryant et al., 2009, El-Khamisy et al., 2003). The limit of this approach might be explained
PARylation response to programmed DNA damage
A prominent feature of many proteins that process DNA strand breaks is their involvement in physiological pathways that respond to programmed DNA damage. Programmed DNA DSBs arise as intermediates during somatic recombination in B and T lymphocytes, spermatogenesis, apoptotic cell death or retroviral integration. These pathways are also intensively studied because defects in one or the other of the repair proteins are often associated with various disorders including immunodeficiency,
Concluding remarks
Research over the last decades has provided ample evidence that DNA damage-induced PARylation is one of the earliest driving force coordinating the detection of the lesions with their signaling and repair. Consequently, inhibiting PARylation represents nowadays one of the most pervasive therapeutic opportunity (i) to potentiate the cytotoxic action of radio- or chemotherapy, (ii) or to sensitize repair-deficient tumours in a synthetic lethality approach. We refer the readers to the review by
Acknowledgments
The authors wish to thank N. Curtin for critical reading of the manuscript. We also thank l’Agence Nationale pour la recherche, le Centre National de la Recherche Scientifique, l’Université de Strasbourg, l’Institut National de la Santé et de la Recherche Médicale et la Ligue Nationale Contre le Cancer (Equipe Labellisée) for financial support.
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2018, Biochimica et Biophysica Acta - Gene Regulatory MechanismsCitation Excerpt :Poly(ADP-ribosyl)ation (PARylation) is one of such modifications performed by poly(ADP-ribose) polymerases (PARPs) [14, 15]. Phylogenetically ancient PARylation is involved in the regulation of numerous cellular functions, such as DNA repair, replication, transcription, translation, telomere maintenance and chromatin remodeling [16–19]. A growing body of evidence demonstrates the link between CTCF PARylation and its biological functions.
Expanding functions of ADP-ribosylation in the maintenance of genome integrity
2017, Seminars in Cell and Developmental BiologyCitation Excerpt :While in vitro studies revealed a role of PARP1 in the mismatch-dependence of 5′-directed excision, its exact role in mismatch repair remains to be characterized [41]. Although several studies have implicated PARP1 in C-NHEJ suggested by its physical and functional interaction with DNA-PKcs or the Ku heterodimer and the early recruitment of the MRN complex at DSBs, yet its contribution remains unclear [42,43]. It was recently claimed that PARP1 is required for the PAR-dependent recruitment of the RNA processing factor RBM14 on DSBs [44].
Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences
2016, Toxicology LettersCitation Excerpt :Importantly, DNA damage-induced PARylation is transient and highly dynamic, since PAR is rapidly hydrolyzed by poly(ADP-ribose) glycohydrolase (PARG) and other PAR-degrading enzymes (Barkauskaite et al., 2013; Hottiger, 2015; Martello et al., 2013). PARylation exerts pleiotropic functions in genome maintenance, but also in a host of other cell functions such as chromatin remodeling, transcription, intra-cellular signaling, cell cycle control, epigenetics and regulation of cell death (Beneke, 2012; Kraus and Hottiger, 2013; Robert et al., 2013). On an organismic level, these functions link PARylation to mechanisms of inflammation and metabolism as well as tumor suppression, for which PARP inhibitors are currently being tested in tumor therapy (Bai and Virag, 2012b; Curtin and Szabo, 2013; Mangerich and Bürkle, 2011, 2012).
RecQ helicases and PARP1 team up in maintaining genome integrity
2015, Ageing Research ReviewsCitation Excerpt :Other family members exhibit mono(ADP-ribosyl)ation activity or are catalytically inactive (reviewed in Hottiger et al., 2010). PARP1 is the founding member of the family and upon induction of DNA damage, in particular DNA strand breaks, PARP1 is responsible for the bulk of cellular PAR synthesis leading to a rise in PAR levels of up to ∼100-fold with >100,000 PAR chains present in each cell (Martello et al., 2013; Robert et al., 2013). The finding that Parp1−/− mice still synthesize PAR, led to the identification of other DNA-damage dependent PARPs, such as PARP2 and later on PARP3 (Shieh et al., 1998).