Identification and characterization of a small inhibitory peptide that can target DNA-PKcs autophosphorylation and increase tumor radiosensitivity

Xiaonan Sun, Chunying Yang, Hai Liu, Qi Wang, Shi Xiu Wu, Xia Li, Tian Xie, Kathryn L. Brinkman, Bin S. Teh, E. Brian Butler, Bo Xu, Shu Zheng

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Purpose: The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR. Methods and Materials: We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair. Results: We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged γ-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells. Conclusions: The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

Original languageEnglish (US)
Pages (from-to)1212-1219
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Issue number5
StatePublished - Dec 1 2012


  • DNA-PKcs
  • Peptides
  • Radiosensitivity

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation
  • Cancer Research


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