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.
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