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An amino-terminal motif functions as a second nuclear export sequence in BRCA1
Marilyn E Thompson1, Cheryl L Robinson-Benion, Jeffrey T Holt
1Department of Biochemistry, Meharry Medical College, 1005 D.B. Todd Boulevard, Nashville, TN 37208, USA. methompson@mmc.edu
The Journal of Biological Chemistry
|April 7, 2005
Summary
Breast cancer susceptibility gene 1 (BRCA1) has a second nuclear export sequence (NES) at amino acid residues 22-30. This finding, along with the previously known NES, explains BRCA1
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Mutations in BRCA1 are linked to hereditary breast and ovarian cancers.
- BRCA1 is primarily a nuclear protein, but can be found in the cytoplasm.
- Leptomycin B treatment causes BRCA1 to accumulate in the nucleus, indicating active nuclear export.
Purpose of the Study:
- To investigate if BRCA1 possesses multiple nuclear export sequences (NES).
- To identify and characterize a potential second NES in BRCA1.
- To understand the role of these NES in BRCA1's cellular localization.
Main Methods:
- Utilized the human immunodeficiency virus-1 Rev complementation assay.
- Introduced mutations in identified NES sequences within BRCA1 cDNA.
- Analyzed BRCA1 cellular localization in transfected MCF-7 cells.
Main Results:
- Identified a novel NES in BRCA1 at amino acid residues 22-30.
- This novel NES demonstrated export capability comparable to the previously known NES (residues 81-99).
- Mutating leucine 28 in the novel NES reduced nuclear export by approximately 75%, causing nuclear accumulation of BRCA1.
Conclusions:
- BRCA1 contains at least two distinct leucine-dependent nuclear export sequences.
- These NES play a crucial role in regulating BRCA1's cellular localization.
- Understanding BRCA1's nuclear export mechanisms is vital for cancer research.