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PMID: 15668392 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 5 ·2005-02-01 ·Pages 1590-5

Reina-San-Martin B, Nussenzweig MC, Nussenzweig A, Difilippantonio S

Abstract

Mre11, Rad50, and Nbs1 form an evolutionarily conserved protein complex (Mre11-Rad50-Nbs1, MRN) that has been proposed to function as a DNA damage sensor. Hypomorphic mutations in Mre11 and Nbs1 result in the human ataxia-telangiectasia-like disorder and Nijmegen breakage syndrome (NBS), respectively. In contrast, complete inactivation of Mre11, Rad50, or Nbs1 leads to early embryonic lethality, suggesting that the hypomorphic mutations may fail to reveal some of the essential functions of MRN. Here, we use Cre-loxP-mediated recombination to restrict Nbs1 deletion to B lymphocytes. We find that disruption of Nbs1 results in the accumulation of high levels of spontaneous DNA damage, impaired proliferation, and chromosomal endoreduplication. Moreover, we show that Ig class-switch recombination (CSR) is diminished in Nbs1-deficient B cells. The CSR defect is B cell-intrinsic, independent of switch-region transcription, and a consequence of inefficient recombination at the DNA level. Our findings reveal that Nbs1 is critical for efficient Ig CSR and maintenance of the integrity of chromosomal structure and number.

MeSH Terms
Animals B-Lymphocytes/cytology,immunology Cell Culture Techniques Cell Cycle Proteins/genetics,immunology Chromosome Mapping DNA-Binding Proteins Flow Cytometry Genomic Instability/immunology Immunoglobulin Switch Region/genetics Mice Mice, Knockout Nuclear Proteins/deficiency,genetics,immunology Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction S Phase
Chemicals
Cell Cycle Proteins DNA-Binding Proteins Nijmegen breakage syndrome 1 protein, mouse Nuclear Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Reina-San-Martin Bernardo
Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA.
Nussenzweig Michel C
Nussenzweig André
Difilippantonio Simone
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0406289102
Published
2005-02-01
Epub
2005-00-24
Pages
1590-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC547831
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0406289102 PMC Full Text View journal details
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