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

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Июнь 12, 2020

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

Язык: Английский

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Non-coding driver mutations in human cancer

Nature reviews. Cancer, Год журнала: 2021, Номер 21(8), С. 500 - 509

Опубликована: Июль 6, 2021

Язык: Английский

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An extended APOBEC3A mutation signature in cancer

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Март 11, 2021

Abstract APOBEC mutagenesis, a major driver of cancer evolution, is known for targeting TpC sites in DNA. Recently, we showed that APOBEC3A (A3A) targets DNA hairpin loops. Here, show secondary structure fact an orthogonal influence on A3A substrate optimality and, surprisingly, can override the sequence preference. VpC (non-TpC) optimal hairpins outperform as mutational hotspots. This expanded understanding mutagenesis illuminates genomic Twin Paradox, puzzling pattern closely spaced mutation hotspots genomes, which one canonical site but other site, and double mutants are seen only trans , suggesting two-hit event. Our results clarify this paradox, revealing both these twins substrates. findings reshape notion signature, highlighting additive roles played by structure.

Язык: Английский

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DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers

Nature Genetics, Год журнала: 2020, Номер 52(9), С. 958 - 968

Опубликована: Авг. 3, 2020

Язык: Английский

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Computational analysis of cancer genome sequencing data

Nature Reviews Genetics, Год журнала: 2021, Номер 23(5), С. 298 - 314

Опубликована: Дек. 8, 2021

Язык: Английский

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