BRCA1 is a multi-functional breast and ovarian cancer suppression gene that is suspected of operating in this manner by suppressing the development of genome disorder. But how it delivers signals that elicit a clinical cancer suppressing effect is unknown. During the current granting period, we reported that the BRCA1 protein (aka B1), itself, executes at least one of its multiple biochemical functions under tight control afforded bya B1-bound, multi-subunit protein complex, called RAP80. This larger complex is called the RAP80/B1 complex, and it allows B1 to perform at normal amplitude error-free double strand DNA break (DSB) repair by homologous recombination(HR). Thus, RAP80/B1 physiologically regulates B1 HR function, which is a known contributor to B1 cancer suppression. This process is termed `HR tuning'. We have also reported that there is another protein present in RAP80/B1 complexes, i.e. the enzyme PARP1. In these complexes, PARP1 selectively poly-ADP ribosylates (parsylates) the DNA binding domain of B1 to form a parsylated derivative, aka B1pars. RAP80/B1 complex formation and proper B1 parsylation contribute to B1 HR and B1 genome stability control. All of these events take place in and require the operation of specialized, DSB- containing nuclear focal structures (aka IRIF) that form after DNA damage. In this proposal, we will determine: a) whether PARP1-catalyzed B1 parsylation regulates any of the other, known functions of B1, including cancer suppression; b) how the specific PARP1-driven parsylation of B1 is directed to its DNA binding domain; c) whether defects in B1 parsylation and RAP80/B1pars complex formation elicit clinically important contributions to sporadic breast and ovarian cancer development; and d) whether they dictate a specific strategy for achieving effective breast and ovarian cancer therapy.

Public Health Relevance

BRCA1 is a powerful breast and ovarian cancer suppressor gene. It operates by suppressing chromosomal disorder. BRCA1 cancer is known to arise in women who inherit a BRCA1 loss of function mutation in the germ line and in whose cancers BRCA1 function is lost. Here we describe results that suggest a second BRCA1 cancer-associated paradigm. Specifically, genome disorder and cancer also arise when the BRCA1 gene is inherited intact, but physiological regulation of one of the DNA repair functions of its tumor-suppressing protein is lost. Our findings also predict a novel approach to the therapy of these cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136512-08
Application #
9399619
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Pelroy, Richard
Project Start
2009-07-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
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 57:636-47
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