Research in the Molecular Pathogenesis is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Currently under investigation are the inherited breast and ovarian cancer genes, BRCA1 and BRCA2. The biological function of these proteins is currently unknown. Previously, we discovered which proteins specifically interact with BRCA1. In the past year we have found that BRCA1 is important for controlling the expression of other genes and is plays a role in DNA repair. Recent experiments have revealed that BRCA1 appears to help in the process of recognizing and eliminating cells that may progress to form tumors. We now know that the increase in breast, ovarian and prostate cancer risk associated with genetic variants in these genes is due to a failure of these mutated proteins to function in the DNA repair pathway. We are using yeast cells as an experimental model to test the functional consequences of mutations found in humans. We have also developed a system for identifying proteins that interact with BRCA1. It is also known that BRCA1 acts to transfer the protein ubiquitin onto other proteins. Through this action BRCA1 may be transferring a signal to start the DNA repair process. The identity of the protein to which this transfer occurs is unknown. We plan to identify these target proteins. We developed two systems capable of measuring this activity of BRCA1. If successful, these systems will allow use to identify specific proteins involved in breast tumor formation. An increased understanding of the BRCA1 and BRCA2 genes will lead to improved diagnostic procedures and possible preventative therapies.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Intramural Research (Z01)
Project #
1Z01HG000120-08
Application #
6988627
Study Section
(GTB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Human Genome Research
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Alter, Blanche P; Rosenberg, Philip S; Brody, Lawrence C (2007) Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 44:1-9
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Coyne, Robert S; McDonald, Heather B; Edgemon, Keith et al. (2004) Functional characterization of BRCA1 sequence variants using a yeast small colony phenotype assay. Cancer Biol Ther 3:453-7
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Tian, H; Brody, L C; Landers, J P (2000) Rapid detection of deletion, insertion, and substitution mutations via heteroduplex analysis using capillary- and microchip-based electrophoresis. Genome Res 10:1403-13

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