TNKS1BP1 functions in DNA double-strand break repair though facilitating DNA-PKcs autophosphorylation dependent on PARP-1
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Lian-Hong Zou1,2, Zeng-Fu Shang2,3, Wei Tan1,2, Xiao-Dan Liu2, Qin-Zhi Xu2, Man Song2,3, Yu Wang2, Hua Guan2, Shi-Meng Zhang2, Lan Yu4, Cai-Gao Zhong1, Ping-Kun Zhou2,3
1School of Public Heath, Central South University, Changsha, Hunan Province 410078, P. R. China
2Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P. R. China
3School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
4Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ping-Kun Zhou, e-mail: [email protected]
Zeng-Fu Shang, e-mail: [email protected]
Keywords: TNKS1BP1, radiation, DNA-PKcs, DNA repair, poly(ADP-ribosyl)ation
Received: December 14, 2014 Accepted: January 10, 2015 Published: February 04, 2015
TNKS1BP1 was originally identified as an interaction protein of tankyrase 1, which belongs to the poly(ADP-ribose) polymerase (PARP) superfamily. PARP members play important roles for example in DNA repair, telomere stability and mitosis regulation. Although the TNKS1BP1 protein was considered to be a poly(ADP-ribosyl)ation acceptor of tankyrase 1, its function is still unknown. Here we firstly identified that TNKS1BP1 was up-regulated by ionizing radiation (IR) and the depletion of TNKS1BP1 significantly sensitized cancer cells to IR. Neutral comet assay, pulsed-field gel electrophoresis, and γH2AX foci analysis indicated that TNKS1BP1 is required for the efficient repair of DNA double-strand breaks (DSB). The TNKS1BP1 protein was demonstrated to interact with DNA-dependent protein kinase (DNA-PKcs) and poly(ADP-ribose) polymerase 1 (PARP-1), by co-immunoprecipitation analysis. Moreover, TNKS1BP1 was shown to promote the association of PARP-1 and DNA-PKcs. Overexpression of TNKS1BP1 induced the autophosphorylation of DNA-PKcs/Ser2056 in a PARP-1 dependent manner, which contributed to an increased capability of DNA DSB repair. Inhibition of PARP-1 blocked the TNKS1BP1-mediated DNA-PKcs autophosphorylation and attenuated the PARylation of DNA-PKcs. TNKS1BP1 is a newly described component of the DNA DSB repair machinery, which provides much more mechanistic evidence for the rationale of developing effective anticancer measures by targeting PARP-1 and DNA-PKcs.
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