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Molecular and Cellular Biology, March 2007, p. 2253-2265, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01354-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

DNA-Dependent Protein Kinase Catalytic Subunit Is Not Required for Dysfunctional Telomere Fusion and Checkpoint Response in the Telomerase-Deficient Mouse{triangledown}

Richard S. Maser,1,2,{dagger} Kwok-Kin Wong,1,{dagger} Erguen Sahin,1,2 Huili Xia,1 Maria Naylor,1 H. Mason Hedberg,1 Steven E. Artandi,3 and Ronald A. DePinho1,2,4*

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115,1 Departments of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts 02115,2 Department of Medicine, Division of Hematology, and Cancer Biology Program, Stanford School of Medicine, Stanford, California 94305,3 Center for Applied Cancer Science and Belfer Foundation Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 021154

Received 24 July 2006/ Returned for modification 30 August 2006/ Accepted 17 November 2006

Telomeres are key structural elements for the protection and maintenance of linear chromosomes, and they function to prevent recognition of chromosomal ends as DNA double-stranded breaks. Loss of telomere capping function brought about by telomerase deficiency and gradual erosion of telomere ends or by experimental disruption of higher-order telomere structure culminates in the fusion of defective telomeres and/or the activation of DNA damage checkpoints. Previous work has implicated the nonhomologous end-joining (NHEJ) DNA repair pathway as a critical mediator of these biological processes. Here, employing the telomerase-deficient mouse model, we tested whether the NHEJ component DNA-dependent protein kinase catalytic subunit (DNA-PKcs) was required for fusion of eroded/dysfunctional telomere ends and the telomere checkpoint responses. In late-generation mTerc–/– DNA-PKcs–/– cells and tissues, chromosomal end-to-end fusions and anaphase bridges were readily evident. Notably, nullizygosity for DNA Ligase4 (Lig4)—an additional crucial NHEJ component—was also permissive for chromosome fusions in mTerc–/– cells, indicating that, in contrast to results seen with experimental disruption of telomere structure, telomere dysfunction in the context of gradual telomere erosion can engage additional DNA repair pathways. Furthermore, we found that DNA-PKcs deficiency does not reduce apoptosis, tissue atrophy, or p53 activation in late-generation mTerc–/– tissues but rather moderately exacerbates germ cell apoptosis and testicular degeneration. Thus, our studies indicate that the NHEJ components, DNA-PKcs and Lig4, are not required for fusion of critically shortened telomeric ends and that DNA-PKcs is not required for sensing and executing the telomere checkpoint response, findings consistent with the consensus view of the limited role of DNA-PKcs in DNA damage signaling in general.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, M413, Boston, MA 02115. Phone: (617) 632-6085. Fax: (617) 632-6069. E-mail: ron_depinho{at}dfci.harvard.edu.

{triangledown} Published ahead of print on 4 December 2006.

{dagger} These two authors contributed equally to this work.

Molecular and Cellular Biology, March 2007, p. 2253-2265, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01354-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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