Abstract

Germ line mutations in the BRCA1 gene predispose individuals to breast and ovarian cancer. Although, BRCA1 has been implicated in transcriptional control and DNA strand break repair, its precise function is unknown. Our laboratory is focused on the function of nuclear multiprotein complexes. We hypothesize that purification of the BRCA 1 complex(es) and determination of their composition and normal functions will allow us to understand their roles in malignant transformation. We have purified a BRCA1-containing complex from HeLa cells and identified a number of its components as subunits of the chromatin remodeling complex SWI/SNF. We hypothesize that the BRCA1 protein exerts its biological functions through the SWI/SNF complex. The three Aims are designed to provide a thorough physical and functional characterization of the BRCA1-SWI/SNF complex.
Aim 1 will identify the remaining components of the BRCA1 complex, and describes experiments that will begin to define the function of the individual proteins in the BRCA1 complex.
Aim 2 describes a detailed functional analysis of the BRCA1 -SWI/SNF complex in estrogen signaling.
Aim 3 extends the work by analyzing the role of the BRCA1-SWI/SNF complex in tumor suppression and the complex's involvement in DNA repair.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090758-03
Application #
6634012
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mietz, Judy
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$287,094
Indirect Cost

  Institution

Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Gardini, Alessandro; Baillat, David; Cesaroni, Matteo et al. (2014) Genome-wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co-activation. EMBO J 33:890-905
Fortschegger, Klaus; Shiekhattar, Ramin (2011) Plant homeodomain fingers form a helping hand for transcription. Epigenetics 6:4-8
Fortschegger, Klaus; de Graaf, Petra; Outchkourov, Nikolay S et al. (2010) PHF8 targets histone methylation and RNA polymerase II to activate transcription. Mol Cell Biol 30:3286-98
Kumaraswamy, Easwari; Shiekhattar, Ramin (2007) Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase. Mol Cell Biol 27:6733-41
Lee, Min Gyu; Villa, Raffaella; Trojer, Patrick et al. (2007) Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318:447-50
Lee, Min Gyu; Norman, Jessica; Shilatifard, Ali et al. (2007) Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein. Cell 128:877-87
Lee, Min Gyu; Wynder, Christopher; Norman, Jessica et al. (2006) Isolation and characterization of histone H3 lysine 4 demethylase-containing complexes. Methods 40:327-30
Norman, Jessica A; Shiekhattar, Ramin (2006) Analysis of Nedd8-associated polypeptides: a model for deciphering the pathway for ubiquitin-like modifications. Biochemistry 45:3014-9
Guo, Shanchun; Hakimi, Mohamed-Ali; Baillat, David et al. (2005) Linking transcriptional elongation and messenger RNA export to metastatic breast cancers. Cancer Res 65:3011-6
Dong, Yuanshu; Hakimi, Mohamed-Ali; Chen, Xiaowei et al. (2003) Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 12:1087-99

Showing the most recent 10 out of 11 publications