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Richard Baer, Ph.D.
Professor of Pathology
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Research
Summary
Hereditary breast and ovarian cancer poses a major health risk due to its prevalence and the severity of its clinical manifestations. Most cases can be attributed to germline mutations in the BRCA1 tumor susceptibility gene. Since the tumors that arise in these patients typically show loss or inactivation of the other BRCA1 allele, the protein product of BRCA1 is believed to function as a tumor suppressor in normal breast and ovarian tissues. This protein has already been implicated in a remarkably broad spectrum of cellular processes, including RNA transcription, chromatin remodeling, mRNA processing, apoptosis, cell cycle checkpoint control, centrosome amplification, and several distinct pathways of DNA repair. The wealth of potential functions ascribed to BRCA1 has made it difficult to discern which of these are responsible for BRCA1-mediated tumor suppression and to determine the mechanism by which loss of BRCA1 activity leads to carcinogenesis.
To investigate the biochemical functions of BRCA1, we have sought to characterize the protein complexes that it forms in vivo and to define the cellular factors that associate with BRCA1. This work has led to the identification of two novel interacting polypeptides: the BRCA1-associated RING domain (BARD1) protein and the C-terminal interacting protein (CtIP). Initial studies of BARD1 have been especially promising. This protein is structurally related to BRCA1 in that it harbors an N-terminal RING domain and two tandem C-terminal BRCT motifs. Most, if not all, of the cellular pools of BRCA1 and BARD1 polypeptides exist in the form of a heterodimer. The interaction between these proteins is mediated by their respective RING domains and it is ablated by tumorigenic mutations in the RING sequences of BRCA1. Moreover, we have observed both germline and tumor-specific mutations of BARD1 in rare cases of breast, ovarian and endometrial carcinoma. Together, these results suggest that the BRCA1/BARD1 heterodimer is the physiological mediator of BRCA1 functions, including those responsible for tumor suppression.
Recent advances in the field of protein ubiquitination have provided important clues about BRCA1 function. In particular, the RING domain is now recognized as an essential component of many ubiquitin E3 ligases, a large group of enzymatic factors that catalyze the final steps of protein ubiquitination. Indeed, the RING sequences of both BRCA1 and BARD1 have been shown to ubiquitinate model substrates in vitro, and this activity is ablated by tumor-associated missense mutations in the BRCA1 motif. Significantly, the E3 ligase activity of the BRCA1/BARD1 heterodimer is dramatically higher than those of the isolated RING domains from either BRCA1 or BARD1. These important studies have uncovered the first catalytic function for the BRCA1 tumor suppressor, and they provide further evidence that the BRCA1/BARD1 complex is the natural mediator of BRCA1 action. Therefore, direct insights into the mechanism of BRCA1-mediated tumor suppression should emerge from further studies of the BRCA1/BARD1 heterodimer and by identification of its enzymatic substrates.
Current Research:
1. BRCA1 Function in Breast Cancer
three Specific Aims will be pursued. First, the expression and in vivo association of BRCA1 and CtIP will be defined with respect to cell cycle progression and the cellular response to DNA damage. Second, CtIP-deficient mice will be used to investigate the role of CtIP in tumor suppression at the organismal level and in the DNA damage response at the cellular level. Third, the effects of CtIP on CtBP-dependent transcriptional repression and BRCA1-modulated transcriptional activation will be explored. These studies should yield new insights into the function of the BRCT domains with respect to BRCA1-mediated tumor suppression. National Cancer Institute 2/2000-1/2005.
2. The Role of BARD1 in Hereditary Breast Cancer
The major goals of this project are: 1) to define the enzymatic properties and substrates of the BRCA1/BARD1 heterodimer, 2) to examine the regulation of BRCA1/BARD1 enzymatic activity in vivo, and 3) to define the role of BARD1 in the maintenance of chromosome stability. National Cancer Institute 4/2003-3/2008.
http://icg.cpmc.columbia.edu/faculty_Baer.htm
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Selected Publications:
1. Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W. (2003) Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science
302(5652):1972-1975
2. Wu-Baer F, Lagrazon K, Yuan W, Baer R. (2003 ) The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J Biol Chem.
278(37):34743-34746
3. McCarthy EE, Celebi JT, Baer R, Ludwig T. (2003 ) Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Mol Cell Biol.
23(14):5056-5063
4. Baer R, Ludwig T. (2002 ) The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity. Current Opinion Genetic Development (Review)
12(1):86-91
5. Wu-Baer F, Baer R. (2001 ) Effect of DNA damage on a BRCA1 complex. Nature
414(6859):36
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