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.
Kim
Sang Soo
SS
Radiation Medicine Branch, National Cancer Center, Goyang, Korea. sangsookim@ncc.re.kr
Cao
Liu
L
Baek
Hye Jung
HJ
Lim
Sung-Chul
SC
Li
Cuiling
C
Wang
Rui-Hong
RH
Xu
Xiaoling
X
Cho
Kwan Ho
KH
Deng
Chu-Xia
CX
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005720:Gamma Rays; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011833:Radiation Injuries, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000254:growth & development* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases