Coordination of BRCA1/BARD1- and MRE11/RAD50/NBS1-dependent DNA Transactions in Breast Tumor Suppression
Abstract
BRCA1/BARD1 and MRE11/RAD50/NBS1 (MRN) play critical roles in preventing the onset of breast tumorigenesis. This is underscored by the fact that mutations in BRCA1 are associated with the most frequent form of hereditary breast cancer and women who inherit mutations in the BRCA1 gene have an estimated lifetime risk of breast and/or ovarian carcinoma as high as 85%. In addition, mutations in NBS1, RAD50 and Mre11 are associated with increased risk for breast cancer or with sporadic breast tumors. Finally, BRCA1/BARD1 and MRN associate in to form DNA damage-specific complexes, critical for damage checkpoint signaling. To better understand the functional significances of these interactions, we propose to determine how BRCA1/BARD1 and the MRN complex cooperate in the recognition, signaling and repair of DNA damage during DNA replication and at double-stranded breaks (DSBs) induced by DNA damaging agents. We hypothesize that each protein complex influences the behavior of the other on DNA and that the roles of these proteins in the maintenance of genomic stability are ultimately dictated by their dynamic interactions on DNA. The overall objective of this collaborative effort is to understand precisely how BRCA1/BARD1 breast tumor suppressor complex orchestrates DNA transactions critical for genome stability and how this process interfaces with MRN's diverse roles.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2009
- Accession Number
- ADA519536
Entities
People
- Eric Greene
- Jean Gautier
Organizations
- Columbia University