Mechanisms of APOBEC3 mutagenesis in human cancer cells

Nature, Год журнала: 2022, Номер 607(7920), С. 799 - 807

Опубликована: Июль 20, 2022

The APOBEC3 family of cytosine deaminases has been implicated in some the most prevalent mutational signatures cancer1-3. However, a causal link between endogenous enzymes and human cancer genomes not established, leaving mechanisms mutagenesis poorly understood. Here, to investigate mutagenesis, we deleted genes from cell lines that naturally generate APOBEC3-associated over time4. Analysis non-clustered clustered across whole-genome sequences 251 breast, bladder lymphoma line clones revealed APOBEC3A deletion diminished signatures. Deletion both APOBEC3B further decreased mutation burdens, without eliminating them. increased protein levels, activity APOBEC3A-mediated lines. uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas loss translesion polymerase REV1 overall burdens. Together, these data represent direct evidence cells. Our results identify as main driver mutations, indicate can restrain APOBEC3A-dependent while contributing its own smaller burdens dissect translate activities into distinct

Язык: Английский

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Therapy-induced APOBEC3A drives evolution of persistent cancer cells

Nature, Год журнала: 2023, Номер 620(7973), С. 393 - 401

Опубликована: Июль 5, 2023

Язык: Английский

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

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 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.

Язык: Английский

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APOBEC3A catalyzes mutation and drives carcinogenesis in vivo

The Journal of Experimental Medicine, Год журнала: 2020, Номер 217(12)

Опубликована: Сен. 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.

Язык: Английский

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Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Cancer Discovery, Год журнала: 2021, Номер 11(10), С. 2456 - 2473

Опубликована: Май 4, 2021

Abstract APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when expression is induced during cancer development remains to be defined. Here we show that specific genes upregulated breast ductal carcinoma situ, and preinvasive lung lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx invasive non–small cell (NSCLC) lesions. find APOBEC3B exacerbates DNA replication stress chromosomal instability through incomplete genomic DNA, manifested by accumulation mitotic ultrafine bridges 53BP1 nuclear bodies the G1 phase cycle. Analysis NSCLC clinical samples mouse models revealed driving chromosome missegregation. propose functionally onset somatic mutational heterogeneity disease, providing fuel for selection early evolution. Significance: This study reveals dynamics drivers gene disease exacerbation diversity promote article highlighted In Issue feature, p. 2355

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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APOBECs and Herpesviruses

Viruses, Год журнала: 2021, Номер 13(3), С. 390 - 390

Опубликована: Фев. 28, 2021

The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful pathogens, by definition, have evolved strategies to escape restriction the APOBEC enzymes their hosts. HIV-1 related retroviruses are thought be predominant natural substrates due obligate single-stranded (ss)DNA replication intermediates, abundant evidence for cDNA strand C-to-U (genomic G-to-A hypermutation), potent degradation mechanism. In contrast, much lower mutation rates observed in double-stranded herpesviruses has been less compelling. However, recent work revealed that Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), herpes simplex virus-1 (HSV-1) potential cellular enzymes. To prevent APOBEC-mediated these viruses repurposed ribonucleotide reductase (RNR) large subunits directly bind, inhibit, relocalize at least two distinct enzymes—APOBEC3B APOBEC3A. importance this interaction is evidenced genetic inactivation EBV RNR (BORF2), which results infectivity higher levels C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions protect lytic phase intermediates from APOBEC-catalyzed deamination. RNR-APOBEC defines new pathogen-host conflict must win real-time transmission pathogenesis. partial losses over evolutionary time may also benefit providing mutational fuel adaptation.

Язык: Английский

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APOBEC-Induced Mutagenesis in Cancer

Annual Review of Genetics, Год журнала: 2022, Номер 56(1), С. 229 - 252

Опубликована: Авг. 27, 2022

The initiation, progression, and relapse of cancers often result from mutations occurring within somatic cells. Consequently, processes that elevate mutation rates accelerate carcinogenesis hinder the development long-lasting therapeutics. Recent sequencing human cancer genomes has identified patterns mutations, termed signatures, many which correspond to specific environmentally induced endogenous processes. Some most frequently observed signatures are caused by dysregulated activity APOBECs, deaminate cytidines in single-stranded DNA at sequence motifs causing C-to-T C-to-G substitutions. In humans, APOBEC-generated genetic heterogeneity tumor cells contributes carcinogenesis, metastasis, resistance Here, we review current understanding APOBECs' role mutagenesis impact on disease biological influence APOBEC mutagenic capacity.

Язык: Английский

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Prospectively defined patterns of APOBEC3A mutagenesis are prevalent in human cancers

Cell Reports, Год журнала: 2022, Номер 38(12), С. 110555 - 110555

Опубликована: Март 1, 2022

Mutational signatures defined by single base substitution (SBS) patterns in cancer have elucidated potential mutagenic processes that contribute to malignancy. Two prevalent mutational human cancers are attributed the APOBEC3 cytidine deaminase enzymes. Among seven proteins, APOBEC3A is a potent and proposed driver of mutagenesis. In this study, we prospectively examine genome-wide aberrations expressing avian DT40 cells. From whole-genome sequencing, detect hundreds thousands substitutions per genome. The signature includes widespread mutations unique insertion-deletion (indel) consisting largely deletions. This multi-dimensional genomes. Our data further reveal replication-associated mutations, rate stem-loop clustered deamination methylated cytidines. comprehensive mutagenesis tool for future studies biomarker activity cancer.

Язык: Английский

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