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1.
Nature ; 630(8017): 744-751, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38867042

RESUMO

DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.


Assuntos
Dano ao DNA , Reparo do DNA , DNA Polimerase Dirigida por DNA , DNA , Mutagênese , Mutação , Animais , Humanos , Camundongos , Alquilação/efeitos da radiação , Linhagem Celular , DNA/química , DNA/genética , DNA/metabolismo , DNA/efeitos da radiação , Adutos de DNA/química , Adutos de DNA/genética , Adutos de DNA/metabolismo , Adutos de DNA/efeitos da radiação , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Reparo do DNA/genética , Reparo do DNA/fisiologia , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Mutagênese/genética , Mutagênese/efeitos da radiação , Mutação/genética , Mutação/efeitos da radiação , Neoplasias/genética , Transcrição Gênica , Raios Ultravioleta/efeitos adversos
2.
Proc Natl Acad Sci U S A ; 121(20): e2403871121, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38717857

RESUMO

DNA base damage is a major source of oncogenic mutations and disruption to gene expression. The stalling of RNA polymerase II (RNAP) at sites of DNA damage and the subsequent triggering of repair processes have major roles in shaping the genome-wide distribution of mutations, clearing barriers to transcription, and minimizing the production of miscoded gene products. Despite its importance for genetic integrity, key mechanistic features of this transcription-coupled repair (TCR) process are controversial or unknown. Here, we exploited a well-powered in vivo mammalian model system to explore the mechanistic properties and parameters of TCR for alkylation damage at fine spatial resolution and with discrimination of the damaged DNA strand. For rigorous interpretation, a generalizable mathematical model of DNA damage and TCR was developed. Fitting experimental data to the model and simulation revealed that RNA polymerases frequently bypass lesions without triggering repair, indicating that small alkylation adducts are unlikely to be an efficient barrier to gene expression. Following a burst of damage, the efficiency of transcription-coupled repair gradually decays through gene bodies with implications for the occurrence and accurate inference of driver mutations in cancer. The reinitation of transcription from the repair site is not a general feature of transcription-coupled repair, and the observed data is consistent with reinitiation never taking place. Collectively, these results reveal how the directional but stochastic activity of TCR shapes the distribution of mutations following DNA damage.


Assuntos
Dano ao DNA , RNA Polimerase II , Transcrição Gênica , Animais , Humanos , Camundongos , Alquilação , DNA/metabolismo , DNA/genética , Reparo por Excisão , Mutação , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Processos Estocásticos
3.
Nature ; 583(7815): 265-270, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581361

RESUMO

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion1,2. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.


Assuntos
Segregação de Cromossomos/genética , Evolução Molecular , Genoma/genética , Neoplasias/genética , Alelos , Animais , Reparo do DNA , Replicação do DNA , Receptores ErbB/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Mutação , Neoplasias/patologia , Seleção Genética , Transdução de Sinais , Troca de Cromátide Irmã , Transcrição Gênica , Quinases raf/metabolismo , Proteínas ras/metabolismo
4.
Proc Natl Acad Sci U S A ; 115(19): 5034-5039, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29610329

RESUMO

Within the mega-pest lineage of heliothine moths are a number of polyphagous, highly mobile species for which the exchange of adaptive traits through hybridization would affect their properties as pests. The recent invasion of South America by one of the most significant agricultural pests, Helicoverpa armigera, raises concerns for the formation of novel combinations of adaptive genes following hybridization with the closely related Helicoverpa zea To investigate the propensity for hybridization within the genus Helicoverpa, we carried out whole-genome resequencing of samples from six species, focusing in particular upon H. armigera population structure and its relationship with H. zea We show that both H. armigera subspecies have greater genetic diversity and effective population sizes than do the other species. We find no signals for gene flow among the six species, other than between H. armigera and H. zea, with nine Brazilian individuals proving to be hybrids of those two species. Eight had largely H. armigera genomes with some introgressed DNA from H. zea scattered throughout. The ninth resembled an F1 hybrid but with stretches of homozygosity for each parental species that reflect previous hybridization. Regions homozygous for H. armigera-derived DNA in this individual included one containing a gustatory receptor and esterase genes previously associated with host range, while another encoded a cytochrome P450 that confers insecticide resistance. Our data point toward the emergence of novel hybrid ecotypes and highlight the importance of monitoring H. armigera genotypes as they spread through the Americas.


Assuntos
Quimera/genética , Fluxo Gênico , Genoma de Inseto , Proteínas de Insetos/genética , Resistência a Inseticidas/genética , Mariposas/genética , Animais , Especificidade da Espécie
5.
PLoS One ; 13(11): e0197760, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383872

RESUMO

The cotton bollworm, Helicoverpa armigera (Hübner) is one of the most serious insect pest species to evolve resistance against many insecticides from different chemical classes. This species has evolved resistance to the pyrethroid insecticides across its native range and is becoming a truly global pest after establishing in South America and having been recently recorded in North America. A chimeric cytochrome P450 gene, CYP337B3, has been identified as a resistance mechanism for resistance to fenvalerate and cypermethrin. Here we show that this resistance mechanism is common around the world with at least eight different alleles. It is present in South America and has probably introgressed into its closely related native sibling species, Helicoverpa zea. The different alleles of CYP337B3 are likely to have arisen independently in different geographic locations from selection on existing diversity. The alleles found in Brazil are those most commonly found in Asia, suggesting a potential origin for the incursion of H. armigera into the Americas.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Mariposas/genética , Piretrinas/farmacologia , Alelos , Animais , Loci Gênicos , Mariposas/efeitos dos fármacos , Recombinação Genética
6.
PLoS One ; 8(11): e81271, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24278409

RESUMO

Phytochelatins are small cysteine-rich non-ribosomal peptides that chelate soft metal and metalloid ions, such as cadmium and arsenic. They are widely produced by plants and microbes; phytochelatin synthase genes are also present in animal species from several different phyla, but there is still little known about whether these genes are functional in animals, and if so, whether they are metal-responsive. We analysed phytochelatin production by direct chemical analysis in Lumbricus rubellus earthworms exposed to arsenic for a 28 day period, and found that arsenic clearly induced phytochelatin production in a dose-dependent manner. It was necessary to measure the phytochelatin metabolite concentrations directly, as there was no upregulation of phytochelatin synthase gene expression after 28 days: phytochelatin synthesis appears not to be transcriptionally regulated in animals. A further untargetted metabolomic analysis also found changes in metabolites associated with the transsulfuration pathway, which channels sulfur flux from methionine for phytochelatin synthesis. There was no evidence of biological transformation of arsenic (e.g. into methylated species) as a result of laboratory arsenic exposure. Finally, we compared wild populations of earthworms sampled from the field, and found that both arsenic-contaminated and cadmium-contaminated mine site worms had elevated phytochelatin concentrations.


Assuntos
Arsênio/farmacologia , Oligoquetos/efeitos dos fármacos , Oligoquetos/metabolismo , Fitoquelatinas/biossíntese , Sequência de Aminoácidos , Aminoaciltransferases/química , Aminoaciltransferases/genética , Aminoaciltransferases/metabolismo , Animais , Exposição Ambiental , Regulação da Expressão Gênica/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Dados de Sequência Molecular , Oligoquetos/classificação , Oligoquetos/genética , Filogenia , Fitoquelatinas/química , Alinhamento de Sequência
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