Electronic Thesis/Dissertation


Methylation of the tumor suppressor protein, BRCA1, influences its transcriptional cofactor function Open Access

Breast cancer is one of the most frequently occurring cancers in women. Approximately half of hereditary breast cancers have mutations in either BRCA1 or BRCA2. BRCA1 is a multifaceted tumor suppressor protein that has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. This multifunctional nature of BRCA1 is achieved by exerting its many effects through modulation of transcription of various factors. Many cellular modulatory events are dictated by covalent modification of proteins, an important mechanism in regulating protein and genome function; of which protein methylation is an important posttranslational modification with activating or repressive effects. Here we demonstrate that BRCA1 is methylated both in breast cancer cell lines and breast cancer tumor samples at both arginine and lysine residues. Arginine methylation by PRMT1 was observed in vitro and the region of BRCA1 504-802 showed to be highly methylated. Furthermore, we observed the functional role of BRCA1 methylation in protein-DNA interactions in vivo when methylation inhibition resulted in differential BRCA1 binding to several DNA damage response gene promoters. These results suggest that methylation may influence either the ability of BRCA1 to bind to specific promoters or protein-protein interactions which alters the recruitment of BRCA1 to these promoters. Thus, given the importance of BRCA1 to genomic stability, methylation of BRCA1 may ultimately affect the tumor suppressor ability of BRCA1.

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