TNKS1BP1 functions in DNA double-strand break repair though facilitating DNA-PKcs autophosphorylation dependent on PARP-1

Lian Hong Zou, Zeng Fu Shang, Wei Tan, Xiao Dan Liu, Qin Zhi Xu, Man Song, Yu Wang, Hua Guan, Shi Meng Zhang, Lan Yu, Cai Gao Zhong, Ping Kun Zhou

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7011-7022
Number of pages12
JournalOncotarget
Volume6
Issue number9
DOIs
StatePublished - 2015

Keywords

  • DNA repair
  • DNA-PKcs
  • Poly(ADP-ribosyl)ation
  • Radiation
  • TNKS1BP1

ASJC Scopus subject areas

  • Oncology

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    Zou, L. H., Shang, Z. F., Tan, W., Liu, X. D., Xu, Q. Z., Song, M., Wang, Y., Guan, H., Zhang, S. M., Yu, L., Zhong, C. G., & Zhou, P. K. (2015). TNKS1BP1 functions in DNA double-strand break repair though facilitating DNA-PKcs autophosphorylation dependent on PARP-1. Oncotarget, 6(9), 7011-7022. https://doi.org/10.18632/oncotarget.3137