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Impaired skin and mammary gland development and increased gamma-irradiation-induced tumorigenesis in mice carrying a mutation of S1152-ATM phosphorylation site in Brca1.

The tumor suppressor BRCA1 interacts with many proteins and undergoes multiple modifications on DNA damage. ATM, a key molecule of the DNA damage response, phosphorylates S1189 of BRCA1 after gamma-irradiation. S1189 of BRCA1 is known as a unique ATM phosphorylation site in BRCA1 exon 11. To study the functions of ATM-dependent phosphorylation of BRCA1-S1189, we generated a mouse model carrying a mutation of S1152A (S1152 in mouse Brca1 corresponds to S1189 in human BRCA1) by gene targeting. Brca1(S1152A/S1152A) mice were born at the expected ratio, unlike that seen in previous studies of Brca1-null mice. However, 36% of Brca1(S1152A/S1152A) mice exhibited aging-like phenotypes including growth retardation, skin abnormalities, and delay of the mammary gland morphogenesis, with an increase in apoptosis. Mutant mice were hypersensitive to high doses of gamma-irradiation, displaying shortened life span and reduction in intestinal villus size, associated with increased apoptosis. Aging-unaffected 18-month-old Brca1(S1152A/S1152A) female mice also showed mammary gland abnormalities with increased levels of cyclin D1 and phospho-ER-alpha, such as Brca1-Delta11 mutation. On low-dose gamma-irradiation, they suffered a marked increase in tumor formation with an abnormal coat pattern. Furthermore, Brca1(S1152A/S1152A) embryonic fibroblasts failed to accumulate p53 on gamma-irradiation with delayed phosphorylation of p53-S23. These observations indicate that ATM-mediated phosphorylation of S1189 is required for BRCA1 functions in the modulation of DNA damage response and in the suppression of tumor formation by regulating p53 and apoptosis.

Pubmed ID: 19996295


  • Kim SS
  • Cao L
  • Baek HJ
  • Lim SC
  • Li C
  • Wang RH
  • Xu X
  • Cho KH
  • Deng CX


Cancer research

Publication Data

December 15, 2009

Associated Grants

  • Agency: Intramural NIH HHS, Id: Z01 DK056001-09

Mesh Terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • BRCA1 Protein
  • Catalytic Domain
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Gamma Rays
  • Mammary Glands, Animal
  • Mammary Neoplasms, Experimental
  • Mice
  • Mutation
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Radiation Injuries, Experimental
  • Skin
  • Tumor Suppressor Proteins