Poly(ADP-ribosyl)ation affects stabilization of Che-1 protein in response to DNA damage |
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Authors: | Bacalini Maria Giulia Di Lonardo Debora Catizone Angela Ciccarone Fabio Bruno Tiziana Zampieri Michele Guastafierro Tiziana Calabrese Roberta Fanciulli Maurizio Passananti Claudio Caiafa Paola Reale Anna |
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Institution: | Department of Cellular Biotechnologies and Haematology, Section of Clinical Biochemistry, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy. |
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Abstract: | Poly(ADP-ribose) polymerase 1 (PARP-1) catalyzes a post-translational modification that plays a crucial role in coordinating the signalling cascade in response to stress stimuli. During the DNA damage response, phosphorylation by ataxia telangiectasia mutated (ATM) kinase and checkpoint kinase Chk2 induces the stabilization of Che-1 protein, which is critical for the maintenance of G2/M arrest. In this study we showed that poly(ADP-ribosyl)ation, beyond phosphorylation, is involved in the regulation of Che-1 stabilization following DNA damage. We demonstrated that Che-1 accumulation upon doxorubicin treatment is reduced after the inhibition of PARP activity in HCT116 cells and in PARP-1 knock-out or silenced cells. In accordance, impairment in Che-1 accumulation by PARP inhibition reduced Che-1 occupancy at p21 promoter and affected the expression of the corresponding gene. Epistasis experiments showed that the effect of poly(ADP-ribosyl)ation on Che-1 stabilization is independent from ATM kinase activity. Indeed we demonstrated that Che-1 protein co-immunoprecipitates with ADP-ribose polymers and that PARP-1 directly interacts with Che-1, promoting its modification in vitro and in vivo. |
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