Radiation-induced mitotic catastrophe in PARG-deficient cells.
Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in the regulation of chromatin structure, DNA metabolism, cell division and cell death. Through the hydrolysis of poly(ADP-ribose) (PAR), Poly(ADP-ribose) glycohydrolase (PARG) has a crucial role in the control of life-and-death balance following DNA insult. Comprehension of PARG function has been hindered by the existence of many PARG isoforms encoded by a single gene and displaying various subcellular localizations. To gain insight into the function of PARG in response to irradiation, we constitutively and stably knocked down expression of PARG isoforms in HeLa cells. PARG depletion leading to PAR accumulation was not deleterious to undamaged cells and was in fact rather beneficial, because it protected cells from spontaneous single-strand breaks and telomeric abnormalities. By contrast, PARG-deficient cells showed increased radiosensitivity, caused by defects in the repair of single- and double-strand breaks and in mitotic spindle checkpoint, leading to alteration of progression of mitosis. Irradiated PARG-deficient cells displayed centrosome amplification leading to mitotic supernumerary spindle poles, and accumulated aberrant mitotic figures, which induced either polyploidy or cell death by mitotic catastrophe. Our results suggest that PARG could be a novel potential therapeutic target for radiotherapy.
Amé
Jean-Christophe
JC
IREBS-FRE3211 du CNRS, Université de Strasbourg, ESBS, Bd Sébastien Brant, BP 10413, 67412 Illkirch Cedex, France.
Fouquerel
Elise
E
Gauthier
Laurent R
LR
Biard
Denis
D
Boussin
François D
FD
Dantzer
Françoise
F
de Murcia
Gilbert
G
Schreiber
Valérie
V
D018385:Centrosome / Q000502:physiology / Q000528:radiation effects; D002869:Chromosome Aberrations / Q000528:radiation effects; D053960:DNA Breaks / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000502:physiology / Q000528:radiation effects; D008938:Mitosis / Q000235:genetics / Q000528:radiation effects*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000235:genetics*; D016615:Telomere / Q000528:radiation effects
D034741:RNA, Small Interfering; D011064:Poly Adenosine Diphosphate Ribose; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase