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.
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This work was supported by National Institutes of Health (CA166677) and the Cancer Prevention Research Institute of Texas (RP110465) to BPC. We thank Dr Titia de Lange for kindly providing anti-TRF1 antibody, and Dr Damiana Chiavolini for critical reading and editing of the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Zhang, S., Matsunaga, S., Lin, YF. et al. Spontaneous tumor development in bone marrow-rescued DNA-PKcs3A/3A mice due to dysfunction of telomere leading strand deprotection. Oncogene 35, 3909–3918 (2016). https://doi.org/10.1038/onc.2015.459
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