Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response

Nature. 2000 Jul 13;406(6792):210-5. doi: 10.1038/35018134.

Abstract

BRCA1 encodes a familial breast cancer suppressor that has a critical role in cellular responses to DNA damage. Mouse cells deficient for Brca1 show genetic instability, defective G2-M checkpoint control and reduced homologous recombination. BRCA1 also directly interacts with proteins of the DNA repair machinery and regulates expression of both the p21 and GADD45 genes. However, it remains unclear how DNA damage signals are transmitted to modulate the repair function of BRCA1. Here we show that the BRCA1-associated protein CtIP becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase (ATM) that is mutated in the disease ataxia telangiectasia. ATM phosphorylates CtIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CtIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. We conclude that ATM, by phosphorylating CtIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • BRCA1 Protein / physiology*
  • Carrier Proteins / physiology*
  • Cell Cycle Proteins
  • Cell Line
  • DNA Damage*
  • DNA Repair
  • DNA-Binding Proteins
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Methyl Methanesulfonate
  • Mice
  • Nuclear Proteins / physiology*
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Proteins / genetics
  • Proteins / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Ultraviolet Rays

Substances

  • BRCA1 Protein
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • GADD45 protein
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Proteins
  • Tumor Suppressor Proteins
  • Methyl Methanesulfonate
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • RBBP8 protein, human