Nonhomologous end joining and V(D)J recombination require an additional factor
- Y. Dai*,†,
- B. Kysela‡,
- L. A. Hanakahi§,
- K. Manolis‡,
- E. Riballo‡,
- M. Stumm¶,
- T. O. Harville‖,
- S. C. West§,
- M. A. Oettinger*,**, and
- P. A. Jeggo‡
- *Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; ‡Genome Damage and Stability Unit, University of Sussex, Brighton, East Sussex BN1 9RQ, United Kingdom; §Cancer Research U.K., London Research Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, United Kingdom; ¶Institut für Humangenetik, Universitätsklinikum, 39120 Magdeburg, Germany; ‖Divisions of Allergy, Immunology, and Rheumatology, Arkansas Children's Hospital, University of Arkansas Medical School, Little Rock, AR 72202; and †Department of Genetics, Harvard Medical School, Boston, MA 02115
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Communicated by Frederick M. Ausubel, Harvard Medical School, Boston, MA (received for review December 3, 2002)
Abstract
DNA nonhomologous end-joining (NHEJ) is the major pathway for repairing DNA double-strand breaks in mammalian cells. It also functions to carry out rearrangements at the specialized breaks introduced during V(D)J recombination. Here, we describe a patient with T−B− severe combined immunodeficiency, whose cells have defects closely resembling those of NHEJ-defective rodent cells. Cells derived from this patient show dramatic radiosensitivity, decreased double-strand break rejoining, and reduced fidelity in signal and coding joint formation during V(D)J recombination. Detailed examination indicates that the patient is defective neither in the known factors involved in NHEJ in mammals (Ku70, Ku80, DNA-dependent protein kinase catalytic subunit, Xrcc4, DNA ligase IV, or Artemis) nor in the Mre11/Rad50/Nbs1 complex, whose homologue in Saccharomyces cerevisiae functions in NHEJ. These results provide strong evidence that additional activities are crucial for NHEJ and V(D)J recombination in mammals.
Footnotes
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↵ ** To whom correspondence should be addressed. E-mail: oettinger{at}frodo.mgh.harvard.edu.
- Abbreviations:
- DSB,
- double-strand break;
- RAG,
- recombination-activating gene;
- SJ,
- signal joint;
- CJ,
- coding joint;
- NHEJ,
- nonhomologous end-joining pathway;
- DNA-PK,
- DNA-dependent protein kinase;
- DNA-PKcs,
- DNA-PK catalytic subunit;
- PFGE,
- pulsed-field gel electrophoresis;
- IR,
- ionizing radiation;
- A-T,
- ataxia–telangiectasia
- Copyright © 2003, The National Academy of Sciences
