Elsevier

Biochemical Pharmacology

Volume 84, Issue 2, 15 July 2012, Pages 137-146
Biochemical Pharmacology

Commentary
The diverse roles and clinical relevance of PARPs in DNA damage repair: Current state of the art

https://doi.org/10.1016/j.bcp.2012.03.018Get rights and content

Abstract

Poly(ADP-ribose) polymerase (PARP) catalyzed poly(ADP-ribosyl)ation is one of the earliest post-translational modification of proteins detectable at sites of DNA strand interruptions. The considerable recent progress in the science of PARP in the last decade and the discovery of a PARP superfamily (17 members) has introduced this modification as a key mechanism regulating a wide variety of cellular processes including among others transcription, regulation of chromatin dynamics, telomere homeostasis, differentiation and cell death. However, the most extensive studied and probably the best characterized role is in DNA repair where it plays pivotal roles in the processing and resolution of the damaged DNA. Although much of the focus has been on PARP1 in DNA repair, recent advances highlight the emergence of other DNA-dependent PARPs (i.e. PARP2, PARP3 and possibly Tankyrase) in this process. Here we will summarize the recent insights into the molecular functions of these PARPs in different DNA repair pathways in which they emerge as specific actors. Furthermore, the DNA repair functions of PARP1 have stimulated another area of intense research in the field with the development of potent and selective PARP1 inhibitors to promote genome instability and cell death in tumor cells. Their current use in clinical trials have demonstrated potentiation of antitumoral drugs and cytotoxicity in repair deficient tumor cells.

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

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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.

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