Radiation-induced mitotic catastrophe in PARG-deficient cells

Abstract

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Variations in the mRNA expression of poly(ADP‐ribose) polymerases, poly(ADP‐ribose) glycohydrolase and ADP‐ribosylhydrolase 3 in breast tumors and impact on clinical outcome

“…39 Irradiated PARG-deficient human cells also show increase radiosensitivity and centrosome amplification which was associated with induced polyploidy or cell death by mitotic catastrophe. 40 It is thus tempting to speculate that the reduced levels of PARG transcript might be associated with an increased genetic instability and could be linked to the higher risk of developing metastases seen in the TNBC patients. The balance between PARP and PARG activity has also been shown to be critical for PARP-1-dependent cell death (Parthanatos) that involves the mitochondrial oxidoreductase apoptosis-inducing factor which is a high-affinity poly(ADP)ribose-binding protein 41 and PARG may also be important for the production of monomeric ADP-ribose, which is a trigger of TRPM2-mediated cellular Ca 21 influx which induces cell death.…”

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

“…However, a hypomorphic mutant for the nuclear isoform is viable but is highly sensitive to treatments with alkylating agents and ionizing radiation, implicating nuclear PARG in the maintenance of genome stability (19). Accordingly, PARG is recruited to DNA repair sites through PARP-and PCNA-dependent pathways (20,21) and prevents mitotic catastrophe upon treatments with ionizing irradiation (22). It was also reported recently that BRCA2-deficient cells are exquisitely sensitive to PARG inhibition, suggesting that PARG functionally assists PARPs in preventing deleterious events at the replication fork (23).…”

New Insight on Entangled DNA Repair Pathways: Stable Silenced Human Cells for Unraveling the DDR Jigsaw

“…PARP1 and PARG display opposite enzymatic activities which govern the balance between life and death after DNA injuries. Our knockdown clones clearly demonstrate that PARP1, PARP2, PARP3 and PARG activities contribute to this homeostasis, even in the absence of exogenous genotoxic attack (Ame et al, 2009, Boehler et al, 2011. PARG KD HeLa cells exhibit a stable loss of the three PARG isoforms (nuclear, cytoplasmic and mitochondrial) and a spectacular loss of function.…”

“…Among the targeted genes and in using our approach we have always obtained at least one vector able to impose long-term shut down greater than 80% as compared with control cells (as evidenced by realtime RT-PCR). Using this technology, more than 160 human genes in different human cell models such as HeLa (Ame et al, 2009, Amine et al, 2009, Aressy et al, 2008, Betous et al, 2009, Biard, 2007, Biard et al, 2005, Biard & Angulo, 2007, Boehler et al, 2011, Bouley et al, 2010, Britton et al, 2009a, Despras et al, 2007, Godon et al, 2008, Le May et al, 2010b, Ousset et al, 2010, Pennarun et al, 2008, Pennarun et al, 2010, Wu et al, 2007, U2OS (Betous et al, 2009) and MRC5-V1 (Bouquet et al, 2011, Britton et al, 2009b, Schmutz et al, 2010 cells have been silenced. Our approach has also been successfully tested in other human tumorderived cell lines, such as RKO (Biard & Angulo, 2007), HCT-116 (Aressy et al, 2008), Caco2 (Coant et al, 2010), SH-SY5Y cells (Schulte et al, 2008), MCF7, MDA-MB 231, K562, UT7 (papers in preparation), and even in mouse NIH-3T3 cells (Meulle et al, 2008).…”

“…6). Our aim was to analyze spontaneous and genotoxic-induced genetic instability (Ame et al, 2009, Boehler et al, 2011, Godon et al, 2008. In a preliminary approach, we focused our attention on the requirement of PARP1 in the two SSBR pathways (SPR versus LPR).…”