Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression

Abstract

The ADP ribosyl transferase [poly(ADP-ribose) polymerase] ARTD3 (PARP3) is a newly characterized member of the ARTD(PARP) family that catalyzes the reaction of ADP ribosylation, a key posttranslational modification of proteins involved in different signaling pathways from DNA damage to energy metabolism and organismal memory. This enzyme shares high structural similarities with the DNA repair enzymes PARP1 and PARP2 and accordingly has been found to catalyse poly(ADP ribose) synthesis. However, relatively little is known about its in vivo cellular properties. By combining biochemical studies with the generation and characterization of loss-of-function human and mouse models, we describe PARP3 as a newcomer in genome integrity and mitotic progression. We report a particular role of PARP3 in cellular response to doublestrand breaks, most likely in concert with PARP1. We identify PARP3 as a critical player in the stabilization of the mitotic spindle and in telomere integrity notably by associating and regulating the mitotic components NuMA and tankyrase 1. Both functions open stimulating prospects for specifically targeting PARP3 in cancer therapy. mitotic division | poly(ADP ribosyl)ation | double-strand break repair P oly(ADP ribosyl)ation is a posttranslational modification of proteins mediated by poly(ADP ribose) polymerases (PARPs). PARPs catalyze the transfer and polymerization of ADP ribose units from NAD + to form branched polymers of ADP ribose covalently linked to heterologous acceptor proteins or PARPs themselves. PARP1, the founding and best-studied member of the PARP family, was for a long time considered to be the only enzyme that could generate poly(ADP ribose) polymers. However,

Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs

“…An episomal shRNA system targeting the microprocessor It has been described previously that expressing genetargeting shRNAs from episomal vectors under the control of the H1 promoter is an efficient method of obtaining stable populations of homogenously knockeddown cells (see for instance Biard et al, 2005;Biard, 2007;Le May et al, 2010;Boehler et al, 2011). We constructed a series of such vectors expressing shRNAs targeting either Drosha or DGCR8.…”

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

“…So far PARP-1, PARP-2 and PARP-3 are the only PARP enzymes whose catalytic activity is stimulated by DNA strand breaks suggesting that they function as crucial members in the cellular pathways responding to DNA damage [8][9][10][11].…”

The Hypoxia-Reoxygenation Injury Model

“…Single nucleotide polymorphisms of the PARP gene have been identified, but only few studies found association with functional changes and increased risk of cancer, nephritis or arthritis [43][44][45][46]. DNA repair processes possibly rely on redundant actions of many other components or PARP-1 is substituted by other PARP isoforms [47,48]. On the other hand, the principal role of PARP-1 is indisputable in cell metabolism and oxidative stress-induced cell death.…”