PARPs and the DNA damage response
Cet article passe en revue le rôle des polymérases PARP dans les mécanismes de réponse aux atteintes à l'ADN et analyse les développements actuels d'inhibiteurs de PARP pour le traitement des cancers
ADP-ribosylation is an important posttranslational modification catalyzed by a variety of enzymes, including poly(ADP-ribose) polymerases (PARPs), which use NAD+ as a substrate to synthesize and transfer ADP-ribose units to acceptor proteins. The PARP family members possess a variety of structural domains, span a wide range of functions and localize to various cellular compartments. Among the molecular actions attributed to PARPs, their role in the DNA damage response (DDR) has been widely documented. In particular, PARPs 1-3 are involved in several cellular processes that respond to DNA lesions, which include DNA damage recognition, signaling and repair as well as local transcriptional blockage, chromatin remodeling and cell death induction. However, how these enzymes are able to participate in such numerous and diverse mechanisms in response to DNA damage is not fully understood. Herein, the DDR functions of PARPs 1-3 and the emerging roles of poly(ADP-ribose) polymers (PAR) in DNA damage are reviewed. The development of PARP inhibitors, their applications and mechanisms of action are also discussed in the context of the DDR.
http://carcin.oxfordjournals.org/content/early/2012/03/19/carcin.bgs132.abstract 2012