Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites - In vivo assessment using phospho-specific antibodies

Gatei, M., Shkedy, D., Khanna, K. K., Uziel, T., Shiloh, Y., Pandita, T.K., Lavin, M. F. and Rotman, G. (2001) Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites - In vivo assessment using phospho-specific antibodies. Journal of Biological Chemistry, 276 20: 17276-17280. doi:10.1074/jbc.M011681200

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
UQ59545_OA.pdf Full text (open access) application/pdf 323.85KB 0

Author Gatei, M.
Shkedy, D.
Khanna, K. K.
Uziel, T.
Shiloh, Y.
Pandita, T.K.
Lavin, M. F.
Rotman, G.
Title Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites - In vivo assessment using phospho-specific antibodies
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2001-01-01
Sub-type Article (original research)
DOI 10.1074/jbc.M011681200
Open Access Status File (Publisher version)
Volume 276
Issue 20
Start page 17276
End page 17280
Total pages 5
Place of publication Bethesda
Publisher Amer Soc Biochemistry Molecular Biology Inc.
Collection year 2001
Language eng
Subject C1
321015 Oncology and Carcinogenesis
730108 Cancer and related disorders
Abstract Recent studies have provided evidence that breast cancer susceptibility gene products (Brca1 and Brca2) suppress cancer, at least in part, by participating in DNA damage signaling and DNA repair. Brca1 is hyperphosphorylated in response to DNA damage and co-localizes with Rad51, a protein involved in homologous-recombination, and Nbs1·Mre11·Rad50, a complex required for both homologous-recombination and nonhomologous end joining repair of damaged DNA. Here, we report that there is a qualitative difference in the phosphorylation states of Brca1 between ionizing radiation (IR) and UV radiation. Brca1 is phosphorylated at Ser-1423 and Ser-1524 after IR and UV; however, Ser-1387 is specifically phosphorylated after IR, and Ser-1457 is predominantly phosphorylated after UV. These results suggest that different types of DNA-damaging agents might signal to Brca1 in different ways. We also provide evidence that the rapid phosphorylation of Brca1 at Ser-1423 and Ser-1524 after IR (but not after UV) is largely ataxia telangiectasia mutated (ATM) kinase-dependent. The overexpression of catalytically inactive ATM and Rad3 related (ATR) kinase inhibited the UV-induced phosphorylation of Brca1 at these sites, indicating that ATR controls Brca1 phosphorylation in vivo after the exposure of cells to UV light. Moreover, ATR associates with Brca1; ATR and Brca1 foci co-localize both in cells synchronized in S phase and after exposure of cells to DNA-damaging agents. ATR can itself phosphorylate the region of Brca1 phosphorylated by ATM (Ser-Gln cluster in the C terminus of Brca1, amino acids 1241-1530). However, there are additional uncharacterized ATR phosphorylation site(s) between residues 521 and 757 of Brca1. Taken together, our results support a model in which ATM and ATR act in parallel but somewhat overlapping pathways of DNA damage signaling but respond primarily to different types of DNA lesion.
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 133 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 137 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 15 Aug 2007, 01:53:04 EST