Germline mutations of the BRCA1 gene are a major cause of hereditary breast and ovarian cancer. Woman who carry BRCA1 mutations often develop basal-like breast tumors, an especially lethal form of breast cancer for which there are currently no effective targeted therapies. Thus, an important priority of current research is to determine the mechanisms by which BRCA1 suppresses tumor formation in normal mammary epithelial cells and how these mechanisms are disrupted in BRCA1 mutation carriers. Significantly, the protein product of BRCA1 has been implicated in multiple aspects of the DNA damage response, including homology-directed repair of double-strand DNA breaks, DNA inter-strand crosslink repair, and cell cycle checkpoint control. To understand the role of BRCA1 in these processes, we study the BRCA1 pathway at the biochemical, cellular, and organismal levels. In doing so, we have identified novel components of the pathway, including the BARD1 and CtIP proteins, and we are now characterizing how the various components of the BRCA1 pathway promote genome stability and tumor suppression.
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. 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.
3. Choudhury, A.D., H. Xu, and R. Baer
(2004). Ubiquitination and proteasomal degradation of the BRCA1 tumor suppressor is regulated during cell cycle progression. J. Biol. Chem. 279: 33909-33918.
4. Choudhury, A.D., H. Xu, A.P. Modi, W. Zhang, T. Ludwig, and R. Baer
(2005). Hyperphosphorylation of the BARD1 tumor suppressor in mitotic cells. J. Biol. Chem. 280: 24669-24679.
5. 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.
6. Reid, L.J., R. Shakya, A.P. Modi, M. Lokshin, J.-T. Cheng, M. Jasin, R. Baer
, and T. Ludwig (2008). The E3 ubiquitin ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks. Proc. Natl. Acad. Sci. USA 105: 20876 - 20881.
7. 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.
8. Wu-Baer, F., Ludwig, T., and R. Baer (2010) The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function. Mol. Cell. Biol. 30: 2787-2798.
9. Peterson, S.E., Li, Y., Chait, B.T., Gottesman, M.E., Baer, R.
, and Gautier, J. (2011) Cdk1 uncouples CtIP-dependent resection and Rad51 filament formation during M-phase double-strand break repair. J. Cell Biol. 194: 705-720.
10. Shakya, R., Reid, L.J., Reczek, C.R., Cole, F., Egli, D., Lin, C.-S., deRooij, D.G., Hirsch, S., Ravi, K., Hicks, J.B., Szabolcs, M., Jasin, M., Baer, R.
, and Ludwig, T. (2011) BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334: 525-528.
11. Reczek, C.R., Szabolcs, M., Stark, J.M., Ludwig, T., and Baer, R.
(2013) The interaction between CtIP and BRCA1 is not essential for resection-mediated DNA repair or tumor suppression. J. Cell Biol. 201: 693–707.
Honors and Awards
Postdoctoral Fellowship; Damon Runyon/Walter Winchell Cancer Fund 1983-1985
Postdoctoral Fellowship; Lady Tata Memorial Trust 1990-1992
Junior Faculty Research Award; American Cancer Society 1993-1997
Faculty Research Award; American Cancer Society
BRCA1, breast neoplasm, cell growth regulation, genetic transcription, transcription factor, DNA damage, gene induction /repression, intermolecular interaction, neoplasm /cancer genetics, tumor suppressor protein, immunofluorescence technique, immunoprecip