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Spontaneous tumor development in bone marrow-rescued DNA-PKcs(3A/3A) mice due to dysfunction of telomere leading

S Zhang1,2, S Matsunaga1,3, Y-F Lin1

  • 1Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.

Oncogene
|December 1, 2015
PubMed

Insights

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylation is vital for DNA repair and preventing cancer. Impaired DNA-PKcs function leads to telomere instability and increased tumor development, highlighting its role in genomic integrity.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Phosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at Thr2609 is crucial for DNA repair and stem cell maintenance.
  • Mutant DNA-PKcs(3A/3A) mice exhibit bone marrow failure, necessitating bone marrow transplantation (BMT).

Purpose of the Study:

  • To investigate the role of DNA-PKcs phosphorylation at Thr2609 in telomere maintenance and cancer development.
  • To understand the implications of impaired DNA-PKcs function on genomic stability.

Main Methods:

  • Analysis of DNA-PKcs(3A/3A) mutant mice, including BMT-rescued individuals.
  • Microscopic examination of skin biopsies and primary keratinocytes for γH2AX foci.
  • Assessment of telomere fusion events in DNA-PKcs mutant cells.
  • Investigation of a known DNA-PKcs Thr2609Pro mutation.

Main Results:

  • BMT-rescued DNA-PKcs(3A/3A) mice showed increased spontaneous tumors, particularly skin cancer.
  • Spontaneous γH2AX foci overlapping with telomeres were observed in DNA-PKcs(3A/3A) cells, indicating telomere replication/maturation defects.
  • Elevated telomere fusion frequencies were detected in DNA-PKcs(3A/3A) cells compared to controls.
  • The DNA-PKcs Thr2609Pro mutation similarly impaired telomere maturation.

Conclusions:

  • Functional DNA-PKcs at the T2609 cluster is essential for telomere leading strand maturation.
  • Proper DNA-PKcs function prevents genomic instability and suppresses cancer development.
  • Impaired DNA-PKcs function contributes to telomere dysfunction and oncogenesis.

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