Publication Date:
2003-10-25
Description:
We used a proteomic approach to identify phosphopeptide-binding modules mediating signal transduction events in the DNA damage response pathway. Using a library of partially degenerate phosphopeptides, we identified tandem BRCT (BRCA1 carboxyl-terminal) domains in PTIP (Pax transactivation domain-interacting protein) and in BRCA1 as phosphoserine- or phosphothreonine-specific binding modules that recognize substrates phosphorylated by the kinases ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia- and RAD3-related) in response to gamma-irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1- and phospho-H2AX (gamma-H2AX)-containing nuclear foci, a marker of DNA damage. These findings provide a molecular basis for BRCT domain function in the DNA damage response and may help to explain why the BRCA1 BRCT domain mutation Met1775 --〉 Arg, which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manke, Isaac A -- Lowery, Drew M -- Nguyen, Anhco -- Yaffe, Michael B -- GM60594/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2003 Oct 24;302(5645):636-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14576432" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Motifs
;
Ataxia Telangiectasia Mutated Proteins
;
BRCA1 Protein/*chemistry/*metabolism
;
Caffeine/pharmacology
;
Calorimetry
;
Carrier Proteins/*chemistry/*metabolism
;
Cell Cycle Proteins/antagonists & inhibitors/metabolism
;
Cell Nucleus/metabolism
;
Cytosol/metabolism
;
DNA Damage
;
DNA-Binding Proteins
;
Gamma Rays
;
Humans
;
Nuclear Proteins/*chemistry/*metabolism
;
Peptide Library
;
Phosphopeptides/*metabolism
;
Phosphorylation
;
Phosphoserine/metabolism
;
Phosphothreonine/metabolism
;
Protein Binding
;
Protein Structure, Tertiary
;
Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism
;
Proteomics
;
Signal Transduction
;
Tumor Cells, Cultured
;
Tumor Suppressor Proteins
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
