Search

To cope with the devastating insults constantly inflicted to their genome by intrinsic and extrinsic DNA damaging sources, cells have evolved a sophisticated network of interconnected DNA caretaking mechanisms that will detect, signal and repair the lesions. Among the underlying molecular mechanisms that regulate these events, PARylation catalyzed by Poly(ADP-ribose) polymerases (PARPs), appears as one of the earliest post-translational modification at the site of the lesion that is known to elicit recruitment and regulation of many DNA damage response proteins. In this review we discuss how the complex PAR molecule operates in stress-induced DNA damage signaling and genome maintenance but also in various physiological settings initiated by developmentally programmed DNA breakage. To illustrate the latter, particular emphasis will be placed on the emerging contribution of PARPs to B cell receptor assembly and diversification.

// Olga Karicheva 1 , Jose Manuel Rodriguez-Vargas 1 , Nadege Wadier 1 , Kathline Martin-Hernandez 1 , Romain Vauchelles 2 , Najat Magroun 1 , Agnes Tissier 3 , Valerie Schreiber 1 , Francoise Dantzer 1 1 Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d’Excellence Medalis, UMR7242, Centre National de la Recherche Scientifique/Universite de Strasbourg, Institut de Recherche de l’Ecole de Biotechnologie de Strasbourg, 67412 Illkirch, France 2 Laboratoire de Biophotonique et Pharmacologie, UMR7213, Centre National de la Recherche Scientifique/Universite de Strasbourg, Faculte de Pharmacie, 67401 Illkirch, France 3 EMT and Cancer Cell Plasticity, Laboratoire d’Excellence DevWeCan, Equipe labellisee Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancerologie, UMR INSERM 1052 CNRS 5286, Centre Leon Berard, F-69008 Lyon, France Correspondence to: Francoise Dantzer, email: francoise.dantzer@unistra.fr Keywords: Poly(ADP-ribose) polymerase 3 (PARP3), EMT, TGFβ, ROS, stem cells Received: April 01, 2016 Accepted: August 10, 2016 Published: August 26, 2016 ABSTRACT Several members of the Poly(ADP-ribose) polymerase (PARP) family are essential regulators of genome integrity, actively prospected as drug targets for cancer therapy. Among them, PARP3 is well characterized for its functions in double-strand break repair and mitotis. Here we report that PARP3 also plays an integral role in TGFβ and reactive oxygen species (ROS) dependent epithelial-to-mesenchymal transition (EMT) and stem-like cell properties in human mammary epithelial and breast cancer cells. PARP3 expression is higher in breast cancer cells of the mesenchymal phenotype and correlates with the expression of the mesenchymal marker Vimentin while being in inverse correlation with the epithelial marker E-cadherin. Furthermore, PARP3 expression is significantly upregulated during TGFβ-induced EMT in various human epithelial cells. In line with this observation, PARP3 depletion alters TGFβ-dependent EMT of mammary epithelial cells by preventing the induction of the Snail-E-cadherin axis, the dissolution of cell junctions, the acquisition of cell motility and chemoresistance. PARP3 responds to TGFβ-induced ROS to promote a TG2-Snail-E-cadherin axis during EMT. Considering the link between EMT and cancer stem cells, we show that PARP3 promotes stem-like cell properties in mammary epithelial and breast cancer cells by inducing the expression of the stem cell markers SOX2 and OCT4, by increasing the proportion of tumor initiating CD44 high /CD24 low population and the formation of tumor spheroid bodies, and by promoting stem cell self-renewal. These findings point to a novel role of PARP3 in the control of TGFβ-induced EMT and acquisition of stem-like cell features and further motivate efforts to identify PARP3 specific inhibitors.