Therapy-induced APOBEC3A drives evolution of persistent cancer cells

Nature, Journal Year: 2023, Volume and Issue: 620(7973), P. 393 - 401

Published: July 5, 2023

Language: Английский

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The roles of APOBEC-mediated RNA editing in SARS-CoV-2 mutations, replication and fitness

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Sept. 13, 2022

During COVID-19 pandemic, mutations of SARS-CoV-2 produce new strains that can be more infectious or evade vaccines. Viral RNA arise from misincorporation by RNA-polymerases and modification host factors. Analysis sequence patients showed a strong bias toward C-to-U mutation, suggesting potential mutational role APOBEC cytosine deaminases possess broad anti-viral activity. We report the first experimental evidence demonstrating APOBEC3A, APOBEC1, APOBEC3G edit on specific sites to mutations. However, replication viral progeny production in Caco-2 cells are not inhibited expression these APOBECs. Instead, wild-type APOBEC3 greatly promotes replication/propagation, utilizes APOBEC-mediated for fitness evolution. Unlike random mutations, this study suggests predictability all possible genome APOBECs based UC/AC motifs genomic structure.

Language: Английский

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HPV16 and HPV18 Genome Structure, Expression, and Post-Transcriptional Regulation

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 4943 - 4943

Published: April 29, 2022

Human papillomaviruses (HPV) are a group of small non-enveloped DNA viruses whose infection causes benign tumors or cancers. HPV16 and HPV18, the two most common high-risk HPVs, responsible for ~70% all HPV-related cervical cancers head neck The expression HPV genome is highly dependent on cell differentiation strictly regulated at transcriptional post-transcriptional levels. Both early late transcripts differentially expressed in infected cells intron-containing bicistronic polycistronic RNAs bearing more than one open reading frame (ORF), because usage alternative viral promoters RNA polyadenylation signals. Papillomaviruses proficiently engage splicing to express individual ORFs from transcripts. In this review, we discuss structures updated transcription maps latest research advances understanding cis-elements, intron branch point sequences, RNA-binding proteins regulation processing. Moreover, briefly epigenetic modifications, including methylation possible APOBEC-mediated editing infections carcinogenesis.

Language: Английский

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Lineage-specific intolerance to oncogenic drivers restricts histological transformation

Science, Journal Year: 2024, Volume and Issue: 383(6683)

Published: Feb. 8, 2024

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial types in the lung. Intriguingly, LUAD can histologically transform into SCLC after treatment with targeted therapies. In this study, we designed models follow conversion of found that barrier histological transformation converges on tolerance Myc, which implicate as a lineage-specific driver pulmonary neuroendocrine cell. Histological transformations frequently accompanied by activation Akt pathway. Manipulating pathway permitted Myc an oncogenic driver, producing rare, stem-like cells transcriptionally resemble basal lineage. These findings suggest may require plasticity inherent stem cell, enabling previously incompatible programs.

Language: Английский

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DNA mismatch and damage patterns revealed by single-molecule sequencing

Nature, Journal Year: 2024, Volume and Issue: 630(8017), P. 752 - 761

Published: June 12, 2024

Language: Английский

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Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 18, 2024

Abstract Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. preferentially targets single-stranded DNAs, with a noted affinity for regions that adopt stem-loop secondary structures. However, the detailed substrate preferences have not been fully established, specific influence sequence on deaminase activity remains to be investigated. Here, we find also selectively structures, they distinct from those subjected deamination APOBEC3A. We develop Oligo-seq, an vitro sequencing-based method identify contexts promoting activity. Through this approach, demonstrate is strongly regulated sequences surrounding targeted cytosine. Moreover, structural features responsible their preferences. Importantly, determine APOBEC3B-induced hairpin-forming within tumor genomes differ mutated Together, our study provides evidence can generate mutation landscapes genomes, driven unique selectivity.

Language: Английский

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APOBEC3A deaminates CTG hairpin loops to promote fragility and instability of expanded CAG/CTG repeats

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(2)

Published: Jan. 7, 2025

CAG/CTG repeats are prone to expansion, causing several inherited human diseases. The initiating sources of DNA damage which lead inaccurate repair the repeat tract cause expansions not fully understood. Expansion-prone actively transcribed and forming stable R-loops with hairpin structures on displaced single-stranded (S-loops). We previously determined that by Saccharomyces cerevisiae cytosine deaminase, Fcy1, was required for both fragility instability tracts engaged in R-loops. To determine whether this mechanism is more universal, we expressed cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B), or activation-induced deaminase (AID) our yeast system. show mutagenic activity Apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptides causes instability, A3A having greatest effect followed A3B least from AID. A3A-induced exacerbated enrichment at site. A3B-induced dependent MutLγ nuclease a lesser extent, base excision factors. Deaminase assays substrates containing CTG GTC triplet sequences revealed prefers cytidines within loop, bulges stem alter preferred locations. Analysis RNA expression levels cortex samples brain tissue exhibits its elevated Huntington’s disease (HD) patient samples. These results implicate deamination as potential source HD other expansion disorders.

Language: Английский

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APOBEC3A catalyzes mutation and drives carcinogenesis in vivo

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 217(12)

Published: Sept. 1, 2020

The APOBEC3 family of antiviral DNA cytosine deaminases is implicated as the second largest source mutation in cancer. This mutational process may be a causal driver or inconsequential passenger to overall tumor phenotype. We show that human APOBEC3A expression murine colon and liver tissues increases tumorigenesis. All other members, including APOBEC3B, fail promote formation. Tumor sequences from APOBEC3A-expressing animals display hallmark APOBEC signature mutations TCA/T motifs. Bioinformatic comparisons observed tumors, previously reported APOBEC3B signatures yeast, reanalyzed datasets support cause-and-effect relationships for APOBEC3A-catalyzed deamination mutagenesis driving multiple cancers.

Language: Английский

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APOBEC3A is a prominent cytidine deaminase in breast cancer

PLoS Genetics, Journal Year: 2019, Volume and Issue: 15(12), P. e1008545 - e1008545

Published: Dec. 16, 2019

APOBEC cytidine deaminases are the second-most prominent source of mutagenesis in sequenced tumors. Previous studies have proposed that APOBEC3B (A3B) is major breast cancer (BRCA). We show APOBEC3A (A3A) only whose expression correlates with APOBEC-induced mutation load and A3A responsible for deamination multiple BRCA cell lines. Comparative analysis A3B by qRT-PCR, RSEM-normalized RNA-seq, unambiguous RNA-seq validated use to measure expression, which indicates primary correlate APOBEC-mutation also demonstrate has >100-fold more activity than presence cellular RNA, likely explaining why higher levels contributes less BRCA. Our findings identify as a deaminase cells possibly contributor signature.

Language: Английский

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Landscape and function of multiple mutations within individual oncogenes

Nature, Journal Year: 2020, Volume and Issue: 582(7810), P. 95 - 99

Published: April 8, 2020

Language: Английский

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