Genomic instability is a driving force for tumor initiation and progression. Elucidating the mechanisms by which mammalian cells maintain genomic integrity is the key to understanding the molecular etiology of cancer. Genomic instability often arises from errors in DNA replication and DNA damage repair. Homologous recombinational repair (HRR) plays a critical role in repairing DNA damage with high accuracy, and resolves stalled DNA replication forks to prevent replication errors. In addition, defects in cell cycle control increase the risk of genomic instability. Our long term goal is to understand the molecular mechanisms by which mammalian cells regulate HRR and cell cycle control to protect their genomic integrity. Although many mammalian HRR genes, including BRCA2 and RAD51, have been identified, the complete understanding of the HRR pathway is hindered by the lack of knowledge of other regulatory genes. Because the CDKN1A (Cipl, Wafl, p21) protein plays major roles in many aspects of cell cycle regulation, identification of novel regulatory pathways for p21 function will provide further insight into the mechanisms by which the cell cycle is regulated. BCCIP is a BRCA2 and CDKN1A Interacting Protein. Because of its interactions with proteins in HRR (BRCA2) and cell cycle control (p21), and altered expression in several types of cancer, characterization of BCCIP will provide unique insight into the mechanisms by which mammalian cells protect their genomic integrity. Based on its interactions with BRCA2 and p21, and other preliminary results, we hypothesize that BCCIP plays a critical role in the regulation of HRR and p21 functions. We propose two specific aims to test this hypothesis.
Aim 1 will identify the roles of BCCIP in DNA damage and replication blockage induced HRR, the mechanism by which BCCIP regulates HRR, and roles of cancer bearing BRCA2 mutations on BCCIP-BRCA2 interaction.
Aim 2 will identify the roles of BCCIP-p21 protein interaction in cell cycle regulation, and the roles of BCCIP in the regulation of p21 expression and intra-cellular distribution. Completion of these aims will expand our knowledge of the regulation of HRR and cell cycle, provide insight into the molecular etiology of cancer and new opportunities to combat cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA115488-01
Application #
6955071
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
2005-06-10
Project End
2006-05-31
Budget Start
2005-06-10
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$266,625
Indirect Cost
Name
University of New Mexico
Department
Genetics
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Huhn, S C; Liu, J; Ye, C et al. (2017) Regulation of spindle integrity and mitotic fidelity by BCCIP. Oncogene 36:4750-4766
Yue, Jingyin; Lu, Huimei; Liu, Jingmei et al. (2012) Filamin-A as a marker and target for DNA damage based cancer therapy. DNA Repair (Amst) 11:192-200
Lu, Huimei; Huang, Yi-Yuan; Mehrotra, Sonam et al. (2011) Essential roles of BCCIP in mouse embryonic development and structural stability of chromosomes. PLoS Genet 7:e1002291
Fan, Jinjiang; Wray, Justin; Meng, Xiangbing et al. (2009) BCCIP is required for the nuclear localization of the p21 protein. Cell Cycle 8:3019-24
Rewari, Amar; Lu, Huimei; Parikh, Rahul et al. (2009) BCCIP as a prognostic marker for radiotherapy of laryngeal cancer. Radiother Oncol 90:183-8
Yue, Jingyin; Wang, Qin; Lu, Huimei et al. (2009) The cytoskeleton protein filamin-A is required for an efficient recombinational DNA double strand break repair. Cancer Res 69:7978-85
Liu, Jingmei; Lu, Huimei; Ohgaki, Hiroko et al. (2009) Alterations of BCCIP, a BRCA2 interacting protein, in astrocytomas. BMC Cancer 9:268
Wray, Justin; Liu, Jingmei; Nickoloff, Jac A et al. (2008) Distinct RAD51 associations with RAD52 and BCCIP in response to DNA damage and replication stress. Cancer Res 68:2699-707
Meng, Xiangbing; Yue, Jingyin; Liu, Zhihe et al. (2007) Abrogation of the transactivation activity of p53 by BCCIP down-regulation. J Biol Chem 282:1570-6
Lu, Huimei; Yue, Jingyin; Meng, Xiangbing et al. (2007) BCCIP regulates homologous recombination by distinct domains and suppresses spontaneous DNA damage. Nucleic Acids Res 35:7160-70

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