While a great deal of media and research emphasis has been placed on breast cancer 1
early onset protein (BRCA1) since the discovery of the corresponding gene 20 years ago, there
is still much to understand about its function. The fundamental question of which proteins
BRCA1 acts on to protect cells from cancer remains unanswered. The goal of this proposal is to
apply techniques from biochemistry, genetics, and cell biology to gain insight into which
proteins BRCA1 modifies and the role of these modifications in cancer biology.
BRCA1 catalyzes the covalent attachment of a small signaling protein called ubiquitin
onto other protein substrates. This sends a signal to the cell to repair damaged DNA, thus
protecting cells from carcinogens. Families with destructive BRCA1 mutations have an
increased risk (up to 80%) of developing breast or ovarian cancer. With identification of the
ubiquitination targets we can begin to unravel which are responsible for cancer prevention and
develop less invasive preventative options. The unique approach proposed here combines
several methods to provide both a comprehensive understanding and the molecular details
needed to bring the BRCA1 picture into focus.