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PMID: 17485521 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Intramural

Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis.

The Journal of experimental medicine ·Vol. 204 ·No. 5 ·2007-05-14 ·Pages 1003-11

Difilippantonio S, Celeste A, Kruhlak MJ, Lee Y, Difilippantonio MJ, Feigenbaum L, Jackson SP, McKinnon PJ, Nussenzweig A

Abstract

The chromosomal instability syndromes Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) share many overlapping phenotypes, including cancer predisposition, radiation sensitivity, cell-cycle checkpoint defects, immunodeficiency, and gonadal dysfunction. The NBS protein Nbs1 is not only a downstream target of AT mutated (ATM) kinase but also acts upstream, promoting optimal ATM activation, ATM recruitment to breaks, and ATM accessibility to substrates. By reconstituting Nbs1 knockout mice with bacterial artificial chromosomes, we have assessed the contribution of distinct regions of Nbs1 to the ATM-dependent DNA damage response. We find that T cell and oocyte development, as well as DNA damage-induced G2/M and S phase checkpoint arrest and radiation survival are dependent on the N-terminal forkhead-associated domain, but not on the principal residues phosphorylated by ATM (S278 and S343) or on the evolutionarily conserved C-terminal region of Nbs1. However, the C-terminal region regulates irradiation-induced apoptosis. These studies provide insight into the complex interplay between Nbs1 and ATM in the DNA damage response.

MeSH Terms
Animals Apoptosis/physiology Ataxia Telangiectasia Mutated Proteins Blotting, Western Cell Cycle Proteins/genetics,metabolism Chromosomal Instability/physiology Chromosomes, Artificial, Bacterial DNA Damage/physiology DNA Primers DNA-Binding Proteins/metabolism Fluorescent Antibody Technique Humans Immunoprecipitation In Situ Nick-End Labeling Mice Mice, Knockout Nuclear Proteins/genetics,metabolism Oocytes/growth & development Protein Serine-Threonine Kinases/metabolism Protein Structure, Tertiary T-Lymphocytes/physiology Tumor Suppressor Proteins/metabolism
Chemicals
Cell Cycle Proteins DNA Primers DNA-Binding Proteins NBN protein, human Nuclear Proteins Tumor Suppressor Proteins ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Difilippantonio Simone
Experimental Immunology Branch and 3Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Celeste Arkady
Kruhlak Michael J
Lee Youngsoo
Difilippantonio Michael J
Feigenbaum Lionel
Jackson Stephen P
McKinnon Peter J
Nussenzweig André
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20070319
Published
2007-05-14
Epub
2007-00-03
Pages
1003-11
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118591
Subset
IM
Grants
Cancer Research UK · A5290 · United Kingdom
Intramural NIH HHS · Z99 CA999999 · United States
External Links
PubMed source DOI: 10.1084/jem.20070319 PMC Full Text View journal details
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