Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.
BRCA2 mutations predispose carriers mainly to breast cancer. The vast majority of BRCA2 mutations are predicted to result in a truncated protein product. The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are crucial for BRCA2 function. A series of green fluorescent protein (GFP)-tagged BRCA2 deletion mutants revealed that nuclear localization depends on two nuclear localization signals that reside within the final 156 residues of BRCA2. Consistent with this observation, an endogenous truncated BRCA2 mutant (6174delT) was found to be cytoplasmic. Together, these studies provide a simple explanation for why the vast majority of BRCA2 mutants are nonfunctional: they do not translocate into the nucleus.
Spain
B H
BH
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Larson
C J
CJ
Shihabuddin
L S
LS
Gage
F H
FH
Verma
I M
IM
D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics*; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D019913:Nuclear Localization Signals; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D019913:Nuclear Localization Signals; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors