This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stracker, T. H.
Right arrow Articles by Petrini, J. H. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stracker, T. H.
Right arrow Articles by Petrini, J. H. J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 2009, p. 503-514, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01354-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Artemis and Nonhomologous End Joining-Independent Influence of DNA-Dependent Protein Kinase Catalytic Subunit on Chromosome Stability{triangledown} ,{dagger}

Travis H. Stracker,1 Bret R. Williams,2,{ddagger} Ludovic Deriano,3 Jan W. Theunissen,1,§ Carrie A. Adelman,1 David B. Roth,3 and John H. J. Petrini1*

Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, New York 10065,1 Laboratory of Genetics, University of Wisconsin Medical School, Madison, Wisconsin 53705,2 Kimmel Center for Biology and Medicine of the Skirball Institute and Department of Pathology, New York University School of Medicine, New York, New York 100163

Received 25 August 2008/ Returned for modification 16 September 2008/ Accepted 6 November 2008

Deficiency in both ATM and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is synthetically lethal in developing mouse embryos. Using mice that phenocopy diverse aspects of Atm deficiency, we have analyzed the genetic requirements for embryonic lethality in the absence of functional DNA-PKcs. Similar to the loss of ATM, hypomorphic mutations of Mre11 (Mre11ATLD1) led to synthetic lethality when juxtaposed with DNA-PKcs deficiency (Prkdcscid). In contrast, the more moderate DNA double-strand break response defects associated with the Nbs1{Delta}B allele permitted viability of some Nbs1{Delta}B/{Delta}B Prkdcscid/scid embryos. Cell cultures from Nbs1{Delta}B/{Delta}B Prkdcscid/scid embryos displayed severe defects, including premature senescence, mitotic aberrations, sensitivity to ionizing radiation, altered checkpoint responses, and increased chromosome instability. The known functions of DNA-PKcs in the regulation of Artemis nuclease activity or nonhomologous end joining-mediated repair do not appear to underlie the severe genetic interaction. Our results reveal a role for DNA-PKcs in the maintenance of S/G2-phase chromosome stability and in the induction of cell cycle checkpoint responses.

* Corresponding author. Mailing address: Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, NY 10065. Phone: (212) 639-2927. Fax: (646) 422-2062. E-mail: petrinij{at}mskcc.org

{triangledown} Published ahead of print on 17 November 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142.

§ Present address: Nature Biotechnology, 75 Varick St., 9th Floor, New York, NY 10013.

Molecular and Cellular Biology, January 2009, p. 503-514, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01354-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Attwooll, C. L., Akpinar, M., Petrini, J. H. J. (2009). The Mre11 Complex and the Response to Dysfunctional Telomeres. Mol. Cell. Biol. 29: 5540-5551 [Abstract] [Full Text]  
  • Meek, K., Jutkowitz, A., Allen, L., Glover, J., Convery, E., Massa, A., Mullaney, T., Stanley, B., Rosenstein, D., Bailey, S. M., Johnson, C., Georges, G. (2009). SCID Dogs: Similar Transplant Potential but Distinct Intra-Uterine Growth Defects and Premature Replicative Senescence Compared with SCID Mice. J. Immunol. 183: 2529-2536 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»