Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Abstract

Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

“…Furthermore, it will be important to determine the involvement of further members of the PARP family in the regulation of inflammatory processes. Some of them have already been shown to associate with inflammatory pathologies: such as PARP-2 (reviewed in [35]), PARP-3 [36], tankyrases [79], or PARP-14 [30,31]. Moreover, poly(ADP-ribose) glycohydrolase has been implicated in the regulation of immune functions [80,81] underlining the central role of poly(ADP-ribosyl)ation in inflammation.…”

“…PARPs other than PARP1 may also alter the production of chemokines and cytokines. Deletion of PARP-2 leads to alterations in the transcriptome, notably in the expression of genes involved in inflammatory regulation [reviewed in [35]]. Interestingly there seems to be an overlap with the inflammatory genes dysregulated upon PARP-1 ablation: e.g.…”

Regulation of E2F1-induced apoptosis by poly(ADP-ribosyl)ation

“…PARP2, like PARP1, catalyzes the poly(ADP-ribosyl)ation of several nuclear proteins with nicotinamide adenine dinucleotide (NAD + ) as a substrate. 32,33 Although the majority of Role of PARP1 in E2F1-induced apoptosis A Kumari et al cellular poly(ADP-ribosyl)ation is attributed to PARP1, PARP2 may act as an alternative enzyme, particularly when PARP1 is unavailable. 32,33 Similar to other small-molecule PARP inhibitors, olaparib inhibits not only PARP1 but also PARP2.…”

Radiosensitisation by Poly(ADP-ribose) Polymerase Inhibition

“…In the HeLa cell model used in our laboratory, the lower PARG protein levels seen in the PARP-2 stably depleted cells was a consequence of decreased PARG mRNA level (our unpublished data) suggesting a direct role of PARP-2 in the regulation of the expression of PARG. Indeed, recent reports have revealed that the depletion of PARP-2 modifies the activity of multiple transcription factors and in particular it is involved in the transcriptional regulation of metabolism and oxidative stress responses [55].…”