BRCA1 is a tumor suppressor gene product dedicated to the suppression of breast and ovarian cancer development. It encodes an 1863 residue nuclear protein, p220. p220 makes contributions to multiple forms of genome integrity control, among which is an ability to support the repair of double strand DNA breaks (DSB) by homologous recombination (HR). Much circumstantial evidence suggests a strong correlation between the ability of p220 to support HR and to perform its tumor suppression function, but how the two are connected, biochemically, is unknown. More specifically, what in vivo biochemical functions p220 must execute to perform its tumor suppressing function and how the two sets of functions are connected to one another are also unknown. In this regard, after the generation of DSBs (e.g. by ionizing radiation), p220 is rapidly attracted to these damaged sites and, some time later, concentrates in focal nuclear structures (aka Ionizing Radiation Induced Foci=IRIF) that form at these locations. What functions p220 performs, once concentrated in IRIF, and how, as is suspected, they contribute to tumor suppression are also unknown. Recently, we and others detected a series of specific biochemical steps that allow p220 to gain access to IRIF. They involve the activities of a nuclear, polyubiquitin-binding protein, Rap80, its associated deubiquitinase, BRCC36, and Abraxas, a nuclear protein that serves as a bridge between p220 and Rap80. All concentrate in IRIF and participate in co-concentrating p220. This proposal is aimed at: a) deciphering the specific biochemical events that tether Rap80 to IRIF;b) at understanding the functional significance associated with p220 concentration in IRIF;and c) learning in what ways these events relate to the execution of p220 cancer suppression function.

Public Health Relevance

BRCA1 is a breast and ovarian cancer gene. When it is inherited in a mutated state, women experience a much higher than normal risk of developing one or both of these diseases. This proposal is aimed at understanding how BRCA1 functions inside the nucleus of cells and why, when its function is rendered defective by mutation, cancer cells develop.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136512-04
Application #
8266522
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Pelroy, Richard
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$511,599
Indirect Cost
$219,257
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Wang, Hua; Bierie, Brian; Li, Andrew G et al. (2016) BRCA1/FANCD2/BRG1-Driven DNA Repair Stabilizes the Differentiation State of Human Mammary Epithelial Cells. Mol Cell 63:277-292
Hatchi, Elodie; Skourti-Stathaki, Konstantina; Ventz, Steffen et al. (2015) BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol Cell 57:636-647
Hill, Sarah J; Rolland, Thomas; Adelmant, Guillaume et al. (2014) Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev 28:1957-75
Hill, Sarah J; Clark, Allison P; Silver, Daniel P et al. (2014) BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 34:3828-42
Silver, Daniel P; Livingston, David M (2012) Mechanisms of BRCA1 tumor suppression. Cancer Discov 2:679-84
Hu, Yiduo; Scully, Ralph; Sobhian, Bijan et al. (2011) RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci. Genes Dev 25:685-700