ATM-dependent phosphorylation of nibrin in response to radiation exposure

Gatei, M., Young, D., Cerosaletti, K. M., Desai-Mehta, A., Spring, K., Kozlov, S., Lavin, M. F., Gatti, R. A., Concannon, P. and Khanna, K. (2000) ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nature Genetics, 25 1: 115-119.

Author Gatei, M.
Young, D.
Cerosaletti, K. M.
Desai-Mehta, A.
Spring, K.
Kozlov, S.
Lavin, M. F.
Gatti, R. A.
Concannon, P.
Khanna, K.
Title ATM-dependent phosphorylation of nibrin in response to radiation exposure
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1061-4036
Publication date 2000-01-01
Sub-type Article (original research)
Volume 25
Issue 1
Start page 115
End page 119
Total pages 5
Editor B. Cohen
Place of publication New York
Publisher Nature America
Collection year 2000
Language eng
Subject C1
321011 Medical Genetics
730107 Inherited diseases (incl. gene therapy)
Abstract Mutations in the gene ATM are responsible for the genetic disorder ataxia-telangiectasia (A-T), which is characterized by cerebellar dysfunction, radiosensitivity, chromosomal instability and cancer predisposition. Both the A-T phenotype and the similarity of the ATM protein to other DNA-damage sensors suggests a role for ATM in biochemical pathways involved in the recognition, signalling and repair of DNA double-strand breaks (DSBs). Them are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS). The protein defective in NBS, nibrin (encoded by NBS1), forms a complex with MRE11 and RAD50 (refs 1,2). This complex localizes to DSBs within 30 minutes after cellular exposure to ionizing radiation (1R) and is observed in brightly staining nuclear foci after a longer period of time(3). The overlap between clinical and cellular phenotypes in A-T and NBS suggests that ATM and nibrin may function in the same biochemical pathway. Here we demonstrate that nibrin is phosphorylated within one hour of treatment of cells with IR. This response is abrogated in A-T cells that either do not express ATM protein or express near full-length mutant protein. We also show that ATM physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association as revealed by radiation-induced foci formation. Our data provide a biochemical explanation for the similarity in phenotype between A-T and NBS.
Keyword Genetics & Heredity
Strand Break Repair
Dna-damage Response
Ionizing-radiation
C-abl
Protein
Kinase
Gene
P53
Phenotype
Product
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Tue, 10 Jun 2008, 20:34:15 EST