Spontaneous tumor development in bone marrow-rescued DNA-PKcs3A/3A mice due to dysfunction of telomere leading strand deprotection

S. Zhang, S. Matsunaga, Y. F. Lin, B. Sishc, Z. Shang, J. Sui, H. Y. Shih, Y. Zhao, O. Foreman, M. D. Story, D. J. Chen, B. P C Chen

Research output: Contribution to journalArticle

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Abstract

Phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at the Thr2609 cluster is essential for its complete function in DNA repair and tissue stem cell homeostasis. This phenomenon is demonstrated by congenital bone marrow failure occurring in DNA-PKcs3A/3A mutant mice, which require bone marrow transplantation (BMT) to prevent early mortality. Surprisingly, an increased incidence of spontaneous tumors, especially skin cancer, was observed in adult BMT-rescued DNA-PKcs3A/3A mice. Upon further investigation, we found that spontaneous γH2AX foci occurred in DNA-PKcs3A/3A skin biopsies and primary keratinocytes and that these foci overlapped with telomeres during mitosis, indicating impairment of telomere replication and maturation. Consistently, we observed significantly elevated frequencies of telomere fusion events in DNA-PKcs3A/3A cells as compared with wild-type and DNA-PKcs-knockout cells. In addition, a previously identified DNA-PKcs Thr2609Pro mutation, found in breast cancer, also induces a similar impairment of telomere leading-end maturation. Taken together, our current analyses indicate that the functional DNA-PKcs T2609 cluster is required to facilitate telomere leading strand maturation and prevention of genomic instability and cancer development.Oncogene advance online publication, 30 November 2015; doi:10.1038/onc.2015.459.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Nov 30 2015

Fingerprint

DNA-Activated Protein Kinase
Telomere
Bone Marrow
Catalytic Domain
DNA
Neoplasms
Bone Marrow Transplantation
Genomic Instability
Skin Neoplasms
Keratinocytes
Oncogenes
Mitosis
DNA Repair
Publications
Homeostasis
Stem Cells
Phosphorylation
Breast Neoplasms
Biopsy
Skin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Spontaneous tumor development in bone marrow-rescued DNA-PKcs3A/3A mice due to dysfunction of telomere leading strand deprotection. / Zhang, S.; Matsunaga, S.; Lin, Y. F.; Sishc, B.; Shang, Z.; Sui, J.; Shih, H. Y.; Zhao, Y.; Foreman, O.; Story, M. D.; Chen, D. J.; Chen, B. P C.

In: Oncogene, 30.11.2015.

Research output: Contribution to journalArticle

Zhang, S. ; Matsunaga, S. ; Lin, Y. F. ; Sishc, B. ; Shang, Z. ; Sui, J. ; Shih, H. Y. ; Zhao, Y. ; Foreman, O. ; Story, M. D. ; Chen, D. J. ; Chen, B. P C. / Spontaneous tumor development in bone marrow-rescued DNA-PKcs3A/3A mice due to dysfunction of telomere leading strand deprotection. In: Oncogene. 2015.
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