Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

Oncogene
F DongR J G Haché

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) has an important role in the cellular response to a broad spectrum of DNA lesions. PARP-1 is strongly activated in response to double-stranded DNA breaks (DSBs), yet its contribution to the DSB response is poorly understood. Here we used bleomycin, a radiomimetic that generates DSBs with high specificity to focus on the response of PARP-1 to DSBs. We report that the induction of PARP-1 activity by bleomycin depends on the Ku antigen, a nonhomologous-DNA-End-Joining factor and protein phosphatase 5 (PP5). PARP-1 activation in response to bleomycin was reduced over 10-fold in Ku-deficient cells, whereas its activation in response to U.V. was unaffected. PARP-1 activation was rescued by reexpression of Ku, but was refractory to manipulation of DNA-dependent protein kinase or ATM. Similarly, PARP-1 activation subsequent to bleomycin was reduced 2-fold on ablation of PP5 and was increased 5-fold when PP5 was overexpressed. PP5 seemed to act directly on PARP-1, as its basal phosphorylation was reduced on overexpression of PP5, and PP5 dephosphorylated PARP-1 in vitro. These results highlight the functional importance of Ku antigen and PP5 for PARP-1 activity subsequent to DSBs.

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Citations

Jan 10, 2012·Nucleic Acids Research·Laura SpagnoloLaurence H Pearl
Sep 21, 2011·Trends in Biochemical Sciences·Dong-Hyun Lee, Dipanjan Chowdhury
Sep 25, 2016·Seminars in Cell & Developmental Biology·Harald SchuhwerkZhao-Qi Wang
Jan 1, 2012·Biomolecules·Hui Ling Ko, Ee Chee Ren
Jan 21, 2020·Journal of Cellular and Molecular Medicine·Chuan LiuGuohua Hu
Feb 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yumi JangMihoko Kai
May 9, 2021·Cellular Signalling·Joachim NeumannUlrich Gergs

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