Toward specific functions of poly(ADP-ribose) polymerase-2

Poly(ADP-ribose) polymerase-2 (PARP-2) belongs to a family of enzymes that catalyze poly(ADP-ribosyl)ation of proteins. PARP-1 and PARP-2 are so far the only PARP enzymes whose catalytic activity has been shown to be induced by DNA-strand breaks, providing strong support for key shared functions in the cellular response to DNA damage. Accordingly, clinical trials for cancer, using PARP inhibitors that target the conserved catalytic domain of PARP proteins, are now ongoing. However, recent data suggest unique functions for PARP-2 in specific processes, such as genome surveillance, spermatogenesis, adipogenesis and T cell development. Understanding these physiological roles might provide invaluable clues to the rational development and exploitation of specific PARP-2 inhibitor drugs in a clinical setting and the design of new therapeutic approaches in different pathophysiological conditions.

Introduction

Poly(ADP-ribosyl)ation is an immediate but transient post-translational modification of proteins with a homopolymeric chain of repeating ADP-ribose units, mediated by the poly(ADP-ribose) polymerase (PARP) enzymes. This modification is a dynamic process, as indicated by the short half-life of the ADP-ribose polymer, which is subjected to degradation by poly(ADP-ribose) glycohydrolase (PARG) (Figure 1) [1]. Poly(ADP-ribosyl)ation and PARPs are involved in various cellular processes, including cell survival and death, transcription, DNA repair, telomere integrity and cell division. Accordingly, pharmacological inhibitors of PARP activity have proven to be useful in different pathological conditions [2].

PARPs constitute a superfamily of 17 members sharing a conserved catalytic domain that contains the PARP signature motif, a highly conserved sequence that forms the active site 1, 3, 4. Among these members, PARP-1 (113 kDa), the first PARP to be discovered, and PARP-2 (62 kDa) are so far the only PARP enzymes whose catalytic activity has been shown to be induced by DNA-strand interruptions [5]. Their targets are mainly involved in chromatin structure and DNA metabolism; they include histones, DNA repair proteins and transcription factors, as well as PARP-1 and PARP-2 themselves [1]. However, PARP-2 is less active than PARP-1, contributing only 5% to 10% of the total PARP activity in response to DNA damage [6].

Biochemical and genetic studies have provided strong support for key shared functions of PARP-1 and PARP-2 in the cellular response to DNA damage. Both proteins heterodimerise, share several common nuclear binding partners and have been described as contributors to single strand break repair/base excision repair (SSBR/BER) processes 6, 7. In addition, mice that are doubly deficient for Parp-1 (Parp-1^−/−) and Parp-2 (Parp-2^−/−) are not viable and die at the onset of gastrulation, demonstrating the crucial role of poly(ADP-ribosyl)ation during embryonic development [8]. However, PARP-1 and PARP-2 have different targets both in DNA and in proteins, suggesting that they might have specific functions, which have started to be identified (Table 1).

The aim of this review is to unravel the specific functions of PARP-2. Recent data describing specific roles of PARP-2 in genome surveillance will be discussed, as well as the emergence of specific spontaneous defects in infertility, impaired fat storage capacity and T lymphocyte development in Parp-2^−/− mice. Understanding these physiological roles might provide invaluable clues to the rational development and exploitation of specific PARP-2 inhibitor drugs in a clinical setting and the design of new therapeutic approaches in different pathophysiological conditions, such as cancer and inflammation.