Tuesday, April 16, 2024
4/16/2024
Abstract APOBEC signature mutations (C to T and C to G substitutions in TCA and TCT trinucleotide sequences) comprise the second most abundant mutation signature in human cancers. This signature is caused by aberrant activity of several members of the APOBEC family of cytidine deaminases, which normally function in many cellular processes including the restriction of viruses. Recently, we found that APOBEC3A (A3A) expression is elevated in APOBEC-mutated breast cancer cell lines, resulting in increased cellular cytidine deaminase activity and breast cancer mutagenesis. The objectives of this proposal are to characterize newly identified components of the APOBEC mutation signature, determine how A3A mRNA expression is upregulated in cancer, define proteasomal controls on A3A protein abundance, and characterize DNA repair pathways that limit A3A mutagenesis. Aim1 will determine the causes and consequences of A3A- and APOBEC3B-induced insertion/deletion mutations. Aim 2 will characterize the mechanisms leading to aberrant up-regulation of A3A in breast cancers by identifying the transcription factors and signaling pathways responsible for increasing A3A expression. Additionally, we will investigate the mechanism(s) leading to proteasome-dependent degradation of A3A and assess the mutagenic consequences of defective post- translational control of A3A abundance. Aim3 will characterize anti-mutagenic roles of the homologous recombination proteins BRCA1 and BRCA2 in template switch-mediated bypass of A3A-dependent abasic sites at replication forks. We will determine whether BRCA1 or BRCA2-deficiency elevates APOBEC-induced mutation in human cell lines and genetically define additional proteins involved in the pathway. Successful completion of these aims will enhance our understanding of A3A regulation and its role in cancer etiology. Additionally, these efforts will identify means to limit APOBEC-induced mutagenesis, which could provide therapeutic benefit by limiting continued tumor evolution that leads to drug resistance.
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