Quantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots

Pégah Jalili, Danae Bowen, Adam Langenbucher, Shinho Park, Kevin Aguirre, Ryan B. Corcoran, Angela G. Fleischman, Michael S. Lawrence (), Lee Zou () and Rémi Buisson ()
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Pégah Jalili: University of California Irvine
Danae Bowen: University of California Irvine
Adam Langenbucher: Harvard Medical School
Shinho Park: University of California Irvine
Kevin Aguirre: University of California Irvine
Ryan B. Corcoran: Harvard Medical School
Angela G. Fleischman: University of California Irvine
Michael S. Lawrence: Harvard Medical School
Lee Zou: Harvard Medical School
Rémi Buisson: University of California Irvine

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract APOBEC3A is a cytidine deaminase driving mutagenesis, DNA replication stress and DNA damage in cancer cells. While the APOBEC3A-induced vulnerability of cancers offers an opportunity for therapy, APOBEC3A protein and mRNA are difficult to quantify in tumors due to their low abundance. Here, we describe a quantitative and sensitive assay to measure the ongoing activity of APOBEC3A in tumors. Using hotspot RNA mutations identified from APOBEC3A-positive tumors and droplet digital PCR, we develop an assay to quantify the RNA-editing activity of APOBEC3A. This assay is superior to APOBEC3A protein- and mRNA-based assays in predicting the activity of APOBEC3A on DNA. Importantly, we demonstrate that the RNA mutation-based APOBEC3A assay is applicable to clinical samples from cancer patients. Our study presents a strategy to follow the dysregulation of APOBEC3A in tumors, providing opportunities to investigate the role of APOBEC3A in tumor evolution and to target the APOBEC3A-induced vulnerability in therapy.

Date: 2020
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DOI: 10.1038/s41467-020-16802-8

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