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Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer. | LitMetric

AI Article Synopsis

  • - The study investigates the role of APOBEC3 enzymes in causing specific mutations linked to cancer, particularly focusing on the enzymes APOBEC3A, APOBEC3B, and APOBEC3H, and their contribution to signature C-to-T and C-to-G mutations.
  • - Researchers developed a system using human cell line HAP1 with a modified thymidine kinase gene to measure mutation rates and discovered that APOBEC3A and APOBEC3B significantly increase TK mutations, unlike APOBEC3H.
  • - Analysis of mutations showed a preference for certain DNA motifs by each enzyme, with most cancer samples exhibiting a mix of APOBEC3 signatures, highlighting the combined effect of these enzymes in cancer mutation patterns and suggesting areas for future

Article Abstract

A prominent source of mutation in cancer is single-stranded DNA cytosine deamination by cellular APOBEC3 enzymes, which results in signature C-to-T and C-to-G mutations in TCA and TCT motifs. Although multiple enzymes have been implicated, reports conflict and it is unclear which protein(s) are responsible. Here we report the development of a selectable system to quantify genome mutation and demonstrate its utility by comparing the mutagenic activities of three leading candidates-APOBEC3A, APOBEC3B, and APOBEC3H. The human cell line, HAP1, is engineered to express the thymidine kinase (TK) gene of HSV-1, which confers sensitivity to ganciclovir. Expression of APOBEC3A and APOBEC3B, but not catalytic mutant controls or APOBEC3H, triggers increased frequencies of TK mutation and similar TC-biased cytosine mutation profiles in the selectable TK reporter gene. Whole genome sequences from independent clones enabled an analysis of thousands of single base substitution mutations and extraction of local sequence preferences with APOBEC3A preferring YTCW motifs 70% of the time and APOBEC3B 50% of the time (Y = C/T; W = A/T). Signature comparisons with breast tumor whole genome sequences indicate that most malignancies manifest intermediate percentages of APOBEC3 signature mutations in YTCW motifs, mostly between 50 and 70%, suggesting that both enzymes contribute in a combinatorial manner to the overall mutation landscape. Although the vast majority of APOBEC3A- and APOBEC3B-induced single base substitution mutations occur outside of predicted chromosomal DNA hairpin structures, whole genome sequence analyses and supporting biochemical studies also indicate that both enzymes are capable of deaminating the single-stranded loop regions of DNA hairpins at elevated rates. These studies combine to help resolve a long-standing etiologic debate on the source of APOBEC3 signature mutations in cancer and indicate that future diagnostic and therapeutic efforts should focus on both APOBEC3A and APOBEC3B.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10715669PMC
http://dx.doi.org/10.1371/journal.pgen.1011043DOI Listing

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