Abstract

The hereditary breast and ovarian tumor suppressor protein BRCA1 plays critical roles in DNA repair, cell cycle checkpoint control, and maintenance of genomic stability. We have recently identified several new regulators of BRCA1, which form a novel complex that is involved in the DNA damage induced ubiquitin signaling for BRCA1 recruitment to the DNA damage sites. We named this complex the BRCA1 A complex. The BRCA1 A complex contains at least five different components, Rap80, Abra1, NBA1, BRE and BRCC36. It associates with BRCA1 through an interaction of Abra1 with the BRCA1 C-terminal BRCT domains. We found that four members of the BRCA1 A complex contain ubiquitin-binding motifs and that BRCC36 is a deubiquitinating enzyme. Interestingly the BRCA1 A complex shares striking similarities to the lid of the 19S proteasome regulatory complex. However, the exact role of this complex at DNA damage sites is not known, nor the role of the complex in BRCA1 signaling and tumor suppression is known. We hypothesize that the BRCA1 A complex functions as a deubiquitinating complex to further modify the DNA damage induced poly-ubiquitination at sites of damage for DNA repair and BRCA1 signaling. To test this hypothesis and to determine the potential tumor-suppressing function of the BRCA1 A complex, we will first examine the assembly and function of this complex as a deubiquitinating complex. Secondly we will determine the role of this complex in DNA damage repair and signaling. Finally we will determine whether the BRCA1 A complex plays a critical role in maintaining genomic stability and tumor suppression in vivo through investigations of Abra1-deficient mice. Together, our studies will provide new avenues for understanding the role of BRCA1 in DNA damage response and tumor suppression.

Public Health Relevance

BRCA1 tumor suppressor plays a critical role in tumor suppression of breast and ovarian cancers. Our work on investigating the role of a novel BRCA1 associated complex in DNA damage response and tumor suppression, if successful, will provide novel insights into BRCA1 involved ubiquitin signaling for DNA repair, maintenance of genome stability and tumor suppression. It will provide novel targets for cancer treatment.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155025-05
Application #
8816044
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
2011-03-01
Project End
2016-05-31
Budget Start
2015-03-01
Budget End
2016-05-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Genetics
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Kitami, Kohei; Kitami, Megumi; Kaku, Masaru et al. (2018) BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development. PLoS Genet 14:e1007340
Zhang, Huiyuan; Li, Haiyan S; Hillmer, Emily J et al. (2018) Genetic rescue of lineage-balanced blood cell production reveals a crucial role for STAT3 antiinflammatory activity in hematopoiesis. Proc Natl Acad Sci U S A 115:E2311-E2319
Paul, Atanu; Wang, Bin (2017) RNF8- and Ube2S-Dependent Ubiquitin Lysine 11-Linkage Modification in Response to DNA Damage. Mol Cell 66:458-472.e5
Xu, Shengfeng; Wu, Xiao; Wu, Ling et al. (2017) Abro1 maintains genome stability and limits replication stress by protecting replication fork stability. Genes Dev 31:1469-1482
Ling, Hong; Li, Shan; Wu, Yang et al. (2016) Genetic evaluation of BRCA1 associated a complex genes with triple-negative breast cancer susceptibility in Chinese women. Oncotarget 7:9759-72
Wu, Qian; Paul, Atanu; Su, Dan et al. (2016) Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites. Mol Cell 61:434-448
Wang, Bin (2014) Analyzing cell cycle checkpoints in response to ionizing radiation in mammalian cells. Methods Mol Biol 1170:313-20
Castillo, Andy; Paul, Atanu; Sun, Baohua et al. (2014) The BRCA1-interacting protein Abraxas is required for genomic stability and tumor suppression. Cell Rep 8:807-17
Tian, Fen; Sharma, Shilpy; Zou, Jianqiu et al. (2013) BRCA1 promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade. Proc Natl Acad Sci U S A 110:13558-63
Hu, Xin; Paul, Atanu; Wang, Bin (2012) Rap80 protein recruitment to DNA double-strand breaks requires binding to both small ubiquitin-like modifier (SUMO) and ubiquitin conjugates. J Biol Chem 287:25510-9

Showing the most recent 10 out of 12 publications