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Concept
Poly(ADP-ribose) polymérase
Résumé
Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.
The PARP family comprises 17 members (10 putative). They vary greatly in structure and function within the cell.
PARP1, PARP2, VPARP (PARP4), Tankyrase-1 and -2 (PARP-5a or TNKS, and PARP-5b or TNKS2) have a confirmed PARP activity.
Others include PARP3, , TIPARP (or "PARP7"), PARP8, , PARP10, , PARP12, , , and PARP16.
PARP is composed of four domains of interest: a DNA-binding domain, a caspase-cleaved domain (see below), an auto-modification domain, and a catalytic domain.
The DNA-binding domain is composed of two zinc finger motifs. In the presence of damaged DNA (base pair-excised), the DNA-binding domain will bind the DNA and induce a conformational shift. It has been shown that this binding occurs independent of the other domains. This is integral in a programmed cell death model based on caspase cleavage inhibition of PARP. The auto-modification domain is responsible for releasing the protein from the DNA after catalysis. Also, it plays an integral role in cleavage-induced inactivation.
The main role of PARP (found in the cell nucleus) is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signaling the enzymatic machinery involved in the SSB repair.
Once PARP detects a SSB, it binds to the DNA, undergoes a structural change, and begins the synthesis of a polymeric adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chain, which acts as a signal for the other DNA-repairing enzymes. Target enzymes include DNA ligase III (LigIII), DNA polymerase beta (polβ), and scaffolding proteins such as X-ray cross-complementing gene 1 (XRCC1). After repairing, the PAR chains are degraded via Poly(ADP-ribose) glycohydrolase (PARG).
NAD+ is required as substrate for generating ADP-ribose monomers.
Source officielle
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