Quantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots
| Autor: | Michael S. Lawrence, Angela G. Fleischman, Kevin Aguirre, Shinho Park, Adam Langenbucher, Ryan B. Corcoran, Lee Zou, Danae Bowen, Pégah Jalili, Rémi Buisson |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
General Physics and Astronomy Biochemistry Whole Exome Sequencing 0302 clinical medicine RNA interference Neoplasms 2.1 Biological and endogenous factors Digital polymerase chain reaction Aetiology APOBEC3A lcsh:Science Cancer Multidisciplinary Tumor Biological techniques Cytidine deaminase Gene Expression Regulation Neoplastic RNA editing 030220 oncology & carcinogenesis RNA Interference Biotechnology DNA damage Science Biology General Biochemistry Genetics and Molecular Biology Article Cell Line 03 medical and health sciences Cell Line Tumor Cytidine Deaminase Exome Sequencing Genetics Humans Enzyme Assays Neoplastic RNA Proteins General Chemistry Computational biology and bioinformatics 030104 developmental biology HEK293 Cells Gene Expression Regulation Cancer cell Mutation Cancer research lcsh:Q RNA Editing |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020) Nature Communications Nature communications, vol 11, iss 1 |
| ISSN: | 2041-1723 |
| Popis: | 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. The DNA cytosine deaminases APOBEC3A and APOBEC3B have emerged from cancer genomics studies as drivers of mutation in cancers and tumor heterogeneity. Here the authors present a computational approach to identify the RNA mutations specifically driven by APOBEC3A, and developed an RNA mutation-based assay to quantify ongoing APOBEC3A activity in tumor cells. |
| Databáze: | OpenAIRE |
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