Disease relevance of Parp2

• In a murine model of acute ischemia, caspase-8 is relocated into the nucleus of apoptotic neurons, where it cleaves PARP-2, a member of the poly(ADP-ribose) polymerase family involved in DNA repair [1].
• Differential effect of PARP-2 deletion on brain injury after focal and global cerebral ischemia [2].
• Male PARP-2-/- mice and wild-type (WT) littermates were subjected to either 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h reperfusion, or underwent 10 mins of KCl-induced cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) and 3-day survival [2].
• Our data demonstrate that selective inhibition of PARP-2 activity results in a marked improvement of colonic inflammatory disease in a mouse model of chronic colitis and a normalization of colonic function [3].
• Secretagogue-induced acute pancreatitis was achieved by 12 hourly intraperitoneal injections of cerulein in mice deficient in PARP-1 or PARP-2 genes, and wild-type (WT) littermate mice untreated or treated with PARP activity inhibitors [4].

High impact information on Parp2

• Poly-(ADP-ribose) polymerase-2 (PARP-2) belongs to a large family of enzymes that synthesize and transfer ADP-ribose polymers to acceptor proteins, modifying their functional properties [5].
• In addition, DP thymocytes from Parp-2(-/-) have a reduced expression of T-cell receptor (TCR)alpha and a skewed repertoire of TCRalpha toward the 5' Jalpha segments [5].
• Here we show that inactivation of mouse Parp-2, but not Parp-1, produced a two-fold reduction in CD4(+)CD8(+) double-positive (DP) thymocytes associated with decreased DP cell survival [5].
• Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse [6].
• The DNA damage-dependent poly(ADP-ribose) polymerases, PARP-1 and PARP-2, homo- and heterodimerize and are both involved in the base excision repair (BER) pathway [6].

Biological context of Parp2

• As indicated by site-directed mutagenesis, PARP-2 cleavage occurs preferentially at the LQMD sequence mapped between the DNA binding and the catalytic domains of the protein [1].
• The generation by homologous recombination of deficient mouse models have confirmed the caretaker function of PARP-1 and PARP-2 in mammalian cells under genotoxic stress [7].
• This review summarizes our present knowledge on their physiological role in the cellular response to DNA damage and on the genetic interactions between PARP-1, PARP-2, Atm that play an essential role during early embryogenesis [7].
• Together, these results support the notion that PARP-1 and PARP-2 possess both overlapping and non-redundant functions in the maintenance of genomic stability [6].
• Reporter gene constructs showed that the 113-base pair intergenic region was indeed sufficient for the expression of both genes and revealed the importance of both the TATA and the DSE/Oct-1 expression control elements for the PARP-2 gene transcription [8].

Anatomical context of Parp2

• Finally, we show that murine fibroblasts deficient in PARP-1 or PARP-2 are not affected in the transcription of ribosomal RNAs [9].
• Moreover, Parp-2(-/-) spermatids are severely compromised in differentiation and exhibit a marked delay in nuclear elongation [10].
• Altogether, our findings indicate that, in addition to its well known role in DNA repair, Parp-2 exerts essential functions during meiosis I and haploid gamete differentiation [10].
• Although Parp-2(-/-) spermatocytes exhibit normal telomere dynamics and normal chromosome synapsis, they display defective meiotic sex chromosome inactivation associated with derailed regulation of histone acetylation and methylation and up-regulated X- and Y-linked gene expression [10].
• Endogenous PARP-2 was coimmunoprecipitated from transformed mouse lung epithelial cell (MLE15) extracts with TTF-1 and was identified by mass spectrometry [11].

Other interactions of Parp2

• Here we show that PARP-1 and PARP-2 subnuclear distributions partially overlap, with both proteins accumulating within the nucleolus independently of each other [9].
• We have identified a nuclear localization signal and a nucleolar localization signal within the N-terminal domain of PARP-2 [9].
• Interestingly, the PARP-2 gene lies head to head with the gene encoding the mouse RNase P RNA subunit [8].

Analytical, diagnostic and therapeutic context of Parp2

• After CA/CPR, PARP-2 deletion significantly increased neuronal cell loss in the hippocampal CA1 field (65%+/-36% ischemic neurons) when compared with WT mice (31%+/-33%), with no effect in either striatum or cortex [2].

References