Dr. Richard Baer Research

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Research Summary
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The BRCA1/BARD1 tumor suppressor and hereditary breast cancer.

Germline mutations of the BRCA1 tumor suppressor gene are a major cause of hereditary breast and ovarian cancer. Indeed, women who carry BRCA1 mutations typically develop basal-like breast cancer, an especially lethal subtype of human breast tumors. To determine the mechanisms by which BRCA1 suppresses tumor formation in normal cells and how these mechanisms are disrupted in BRCA1 mutation carriers, we study the functional and pathogenic properties of the BRCA1 protein. In vivo, BRCA1 exists in the form of a heterodimer with another structurally related tumor suppressor, the BARD1 protein [1]. Most of the cellular functions attributed to BRCA1, including its critical activities in genome stability and tumor suppression, are mediated by the BRCA1/BARD1 heterodimer [2,3]. Therefore, we use biochemical, cellular, and organismal approaches to characterize the BRCA1/BARD complex and its associated factors, such as the DNA repair protein CtIP [4-6]. In this manner, we seek to define the biological functions of the BRCA1/BARD1 pathway in normal cells, particularly with respect to maintenance of genome stability, and how the loss of these functions promotes breast and ovarian cancer [7].

  1. Wu, L.C., Z.W. Wang, J.T. Tsan, M.A. Spillman, A. Phung, X.L. Xu, M.-C.W. Yang, L.-Y. Hwang, A.M. Bowcock, and R. Baer (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nature Genet. 14: 430-440.
  2. Laufer, M., S.V. Nandula, A.P. Modi, S. Wang, M. Jasin, V.V.V.S. Murty, T. Ludwig, and R. Baer (2007) Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair. J. Biol. Chem. 282: 34325-34333.
  3. Shakya, R., M. Szabolcs, E.E. McCarthy, E. Ospina, K. Basso, S.V. Nandula, V.V. Murty, R. Baer, and T. Ludwig (2008) The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. Proc. Natl. Acad. Sci. USA 105: 7040-7045.
  4. Yu, X., L.C. Wu, A.M. Bowcock, A. Aronheim, and R. Baer (1998) The carboxy-terminal (BRCT) motifs of BRCA interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273: 25388-25392.
  5. Peterson, S.E., Y. Li, F. Wu-Baer, B.T. Chait, R. Baer, H. Yan, M.E. Gottesman, and J. Gautier (2012) Activation of DSB Processing Requires Phosphorylation of CtIP by ATR. Mol. Cell.
  6. Reczek, C.R., M. Szabolcs, J.M. Stark, T. Ludwig, and R. Baer (2013) The interaction between CtIP and BRCA1 is not essential for resection-mediated DNA repair or tumor suppression. J. Cell Biol. 201: 693-707.
  7. Shakya, R., L.J. Reid, C.R. Reczek, F. Cole, D. Egli, C.-S. Lin, D.G. deRooij, S. Hirsch, R. Kandasamy, J.B. Hicks, M. Szabolcs, M. Jasin, R. Baer, and T. Ludwig (2011) BRCT phosphoprotein recognition, but not E3 ligase activity, is essential for BRCA1 tumor suppression. Science 334: 525-528.