Ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases have overlapping activities during chromosomal signal joint formation

Eric J. Gapud, Yair Dorsett, Bu Yin, Elsa Callen, Andrea Bredemeyer, Grace K. Mahowald, Kazuo Q. Omi, Laura M. Walker, Jeffrey J. Bednarski, Peter J. McKinnon, Craig H. Bassing, Andre Nussenzweig, Barry P. Sleckmana

Research output: Contribution to journalArticle

Abstract

Lymphocyte antigen receptor gene assembly occurs through the process of V(D)J recombination, which is initiated when the RAG endonuclease introduces DNA DSBs at two recombining gene segments to form broken DNA coding end pairs and signal end pairs. These paired DNA ends are joined by proteins of the nonhomologous end-joining (NHEJ) pathway of DSB repair to form a coding joint and signal joint, respectively. RAG DSBs are generated in G1-phase developing lymphocytes, where they activate the ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases to orchestrate diverse cellular DNA damage responses including DSB repair. Paradoxically, although Atm and DNA-PKcs both function during coding joint formation, Atmappears to be dispensible for signal joint formation; and although some studies have revealed an activity for DNA-PKcs during signal joint formation, others have not. Here we show that Atm and DNA-PKcs have overlapping catalytic activities that are required for chromosomal signal joint formation and for preventing the aberrant resolution of signal ends as potentially oncogenic chromosomal translocations.

Original languageEnglish (US)
Pages (from-to)2022-2027
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number5
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

Keywords

  • DNA repair
  • Lymphocyte development
  • Lymphoid tumors

ASJC Scopus subject areas

  • General

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  • Cite this

    Gapud, E. J., Dorsett, Y., Yin, B., Callen, E., Bredemeyer, A., Mahowald, G. K., Omi, K. Q., Walker, L. M., Bednarski, J. J., McKinnon, P. J., Bassing, C. H., Nussenzweig, A., & Sleckmana, B. P. (2011). Ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases have overlapping activities during chromosomal signal joint formation. Proceedings of the National Academy of Sciences of the United States of America, 108(5), 2022-2027. https://doi.org/10.1073/pnas.1013295108