PALB2 links BRCA1 and BRCA2 in the DNA-damage response.
BRCA1 and BRCA2 are often mutated in familial breast and ovarian cancer. Both tumor suppressors play key roles in the DNA-damage response. However, it remains unclear whether these two tumor suppressor function together in the same DNA-damage response pathway. Here, we show that BRCA1 associates with BRCA2 through PALB2/FANCN, a major binding partner of BRCA2. The interaction between BRCA1 and BRCA2 is abrogated in PALB2-deficient Fanconi anemia cells and in the cells depleted of PALB2 by small interfering RNA. Moreover, we show that BRCA1 promotes the concentration of PALB2 and BRCA2 at DNA-damage sites and the interaction between BRCA1 and PALB2 is important for the homologous recombination repair. Taken together, our results indicate that BRCA1 is an upstream regulator of BRCA2 in the DNA-damage response, and PALB2 is the linker between BRCA1 and BRCA2.
Zhang
Feng
F
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, BSRB 1520, Ann Arbor, MI 48109, USA.
Ma
Jianglin
J
Wu
Jiaxue
J
Ye
Lin
L
Cai
Hong
H
Xia
Bing
B
Yu
Xiaochun
X
D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins