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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Cancer driver mutations: predictions and reality

Trends in Molecular Medicine, Год журнала: 2023, Номер 29(7), С. 554 - 566

Опубликована: Апрель 17, 2023

Cancer cells accumulate many genetic alterations throughout their lifetime, but only a few of them drive cancer progression, termed driver mutations. Driver mutations may vary between types and patients, can remain latent for long time become drivers at particular stages, or oncogenesis in conjunction with other The high mutational, biochemical, histological tumor heterogeneity makes mutation identification very challenging. In this review we summarize recent efforts to identify annotate effects. We underline the success computational methods predict finding novel biomarkers, including circulating DNA (ctDNA). also report on boundaries applicability clinical research.

Язык: Английский

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Extrachromosomal DNA amplifications in cancer

Nature Reviews Genetics, Год журнала: 2022, Номер 23(12), С. 760 - 771

Опубликована: Авг. 11, 2022

Язык: Английский

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Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma

Cancer Discovery, Год журнала: 2023, Номер 13(4), С. 880 - 909

Опубликована: Янв. 26, 2023

Blocking cancer genomic instability may prevent tumor diversification and escape from therapies. We show that, after MAPK inhibitor (MAPKi) therapy in patients mice bearing patient-derived xenografts (PDX), acquired resistant genomes of metastatic cutaneous melanoma specifically amplify resistance-driver, nonhomologous end-joining (NHEJ), homologous recombination repair (HRR) genes via complex rearrangements (CGR) extrachromosomal DNAs (ecDNA). Almost all sensitive acquired-resistant harbor pervasive chromothriptic regions with disproportionately high mutational burdens significant overlaps ecDNA CGR spans. Recurrently, somatic mutations within amplicons enrich for HRR signatures, particularly tumors. Regardless sensitivity or resistance, breakpoint-junctional sequence analysis suggests NHEJ as critical to double-stranded DNA break underlying formation. In human cell lines PDXs, targeting by a DNA-PKCS prevents/delays MAPKi resistance reducing the size ecDNAs CGRs early on combination treatment. Thus, causes prevents resistance. Acquired often results heterogeneous, redundant survival mechanisms, which challenge strategies aimed at reversing Acquired-resistant melanomas recurrently evolve resistance-driving resistance-specific CGRs, thereby nominating chromothripsis-ecDNA-CGR biogenesis resistance-preventive target. Specifically, DNA-PKCS/NHEJ suppressing ecDNA/CGR MAPKi-treated melanomas. This article is highlighted Issue feature, p. 799.

Язык: Английский

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Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity

Nature Genetics, Год журнала: 2023, Номер 55(4), С. 607 - 618

Опубликована: Март 16, 2023

Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated transcriptomic epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% interpatient molecular differences. Instead, MESOMICS project paves way morphomolecular MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response CpG island methylator profile. We show these dimensions are complementary, capture major differences delimited by extreme phenotypes that—in case interdependent morphology adapted response—reflect specialization. These findings unearth interplay between functional biology its genomic history, provide insights into variations observed in behavior patients MPM.

Язык: Английский

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Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers

Nature Cancer, Год журнала: 2023, Номер 4(2), С. 276 - 289

Опубликована: Янв. 26, 2023

Abstract Analysis of mutational signatures can reveal underlying molecular mechanisms the processes that have imprinted somatic mutations found in cancer genomes. Here, we analyze single base substitutions and small insertions deletions pediatric cancers encompassing 785 whole-genome sequenced tumors from 27 molecularly defined subtypes. We identified only a number active cancers, compared with previously analyzed adult cancers. Further, report significant difference proportion showing homologous recombination repair defect previous analyses. In leukemias, an indel signature, not reported, characterized by long nonrepeat regions, affecting mainly intronic intergenic but also exons known genes. provide systematic overview COSMIC v.3 across which is highly relevant for understanding tumor biology enabling future research defining biomarkers treatment response.

Язык: Английский

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Extrachromosomal DNA in cancer

Nature reviews. Cancer, Год журнала: 2024, Номер 24(4), С. 261 - 273

Опубликована: Фев. 26, 2024

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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Modern biology of extrachromosomal DNA: A decade-long voyage of discovery

Cell Research, Год журнала: 2025, Номер 35(1), С. 11 - 22

Опубликована: Янв. 3, 2025

Abstract Genomic instability is a hallmark of cancer and major driving force tumorigenesis. A key manifestation genomic the formation extrachromosomal DNAs (ecDNAs) — acentric, circular DNA molecules ranging from 50 kb to 5 Mb in size, distinct chromosomes. Ontological studies have revealed that ecDNA serves as carrier oncogenes, immunoregulatory genes, enhancers, capable elevated transcription its cargo genes heterogeneity, leading rapid tumor evolution therapy resistance. Although was documented over half century ago, past decade has witnessed surge breakthrough discoveries about biological functions. Here, we systematically review modern biology uncovered last ten years, focusing on how during this pioneering stage illuminated our understanding ecDNA-driven transcription, progression. Furthermore, discuss ongoing efforts target novel approach therapy. This burgeoning field entering new phase, poised reshape knowledge therapeutic strategies.

Язык: Английский

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APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer

Nature Genetics, Год журнала: 2023, Номер 55(10), С. 1721 - 1734

Опубликована: Сен. 21, 2023

Abstract The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates cells are not fully delineated. Here proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show binding to R-loops and vitro. Genetic demonstrate increases lacking decreases overexpressing APOBEC3B. Genome-wide analyses major changes the overall landscape physiological stimulus-induced thousands differentially altered regions, as well many these sites. APOBEC3 mutagenesis impacts genes overexpressed tumors splice factor mutant preferentially, APOBEC3-attributed kataegis enriched RTCW motifs consistent deamination. Taken together fact that binds RNA preferentially deaminates DNA, results support mechanism which regulates contributes

Язык: Английский

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