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1.
Nat Commun ; 12(1): 4917, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389714

RESUMO

APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A expression in tumors. In this study, we find that both viral infection and genotoxic stress transiently up-regulate APOBEC3A and pro-inflammatory genes using two distinct mechanisms. First, we demonstrate that STAT2 promotes APOBEC3A expression in response to foreign nucleic acid via a RIG-I, MAVS, IRF3, and IFN-mediated signaling pathway. Second, we show that DNA damage and DNA replication stress trigger a NF-κB (p65/IkBα)-dependent response to induce expression of APOBEC3A and other innate immune genes, independently of DNA or RNA sensing pattern recognition receptors and the IFN-signaling response. These results not only reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A but also highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS.


Assuntos
Citidina Desaminase/genética , Dano ao DNA , Regulação da Expressão Gênica , Imunidade/genética , Proteínas/genética , Transdução de Sinais/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Citidina Desaminase/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células THP-1 , Fator de Transcrição RelA/metabolismo , Regulação para Cima , Vírus/crescimento & desenvolvimento
2.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066960

RESUMO

DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin. We report that RT advances are cell-type-specific and involve large heterochromatin domains. Importantly, we found that some major late to early RT advances can be inherited by the unstressed next-cellular generation, which is a unique process that correlates with enhanced chromatin accessibility, as well as modified replication origin landscape and gene expression in daughter cells. Collectively, this work highlights how low replication stress may impact cellular identity by RT advances events at a subset of chromosomal domains.


Assuntos
Período de Replicação do DNA , Estresse Fisiológico , Afidicolina/farmacologia , Linhagem Celular Tumoral , Cromatina/metabolismo , Dano ao DNA , Período de Replicação do DNA/genética , Epigênese Genética/efeitos dos fármacos , Loci Gênicos , Código das Histonas , Humanos , Modelos Biológicos , Estresse Fisiológico/genética
3.
Nat Commun ; 12(1): 1602, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707442

RESUMO

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


Assuntos
Transformação Celular Neoplásica/genética , Citidina Desaminase/genética , DNA/genética , Antígenos de Histocompatibilidade Menor/genética , Conformação de Ácido Nucleico , Proteínas/genética , Sequência de Bases/genética , Linhagem Celular Tumoral , Escherichia coli/genética , Células HEK293 , Humanos , Mutagênese , Mutação , Neoplasias/genética
4.
Mutat Res ; 808: 62-73, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28843435

RESUMO

Replication stress is a strong and early driving force for genomic instability and tumor development. Beside replicative DNA polymerases, an emerging group of specialized DNA polymerases is involved in the technical assistance of the replication machinery in order to prevent replicative stress and its deleterious consequences. During S-phase, altered progression of the replication fork by endogenous or exogenous impediments induces replicative stress, causing cells to reach mitosis with genomic regions not fully duplicated. Recently, specific mechanisms to resolve replication intermediates during mitosis with the aim of limiting DNA damage transmission to daughter cells have been identified. In this review, we detail the two major actions of specialized DNA polymerases that limit DNA damage transmission: the prevention of replicative stress by non-B DNA replication and the recovery of stalled replication forks.


Assuntos
Dano ao DNA , Reparo do DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Instabilidade Genômica , Humanos
5.
Cell Rep ; 17(7): 1858-1871, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27829156

RESUMO

Cancer cells rely on the activation of telomerase or the alternative lengthening of telomeres (ALT) pathways for telomere maintenance and survival. ALT involves homologous recombination (HR)-dependent exchange and/or HR-associated synthesis of telomeric DNA. Utilizing proximity-dependent biotinylation (BioID), we sought to determine the proteome of telomeres in cancer cells that employ these distinct telomere elongation mechanisms. Our analysis reveals that multiple DNA repair networks converge at ALT telomeres. These include the specialized translesion DNA synthesis (TLS) proteins FANCJ-RAD18-PCNA and, most notably, DNA polymerase eta (Polη). We observe that the depletion of Polη leads to increased ALT activity and late DNA polymerase δ (Polδ)-dependent synthesis of telomeric DNA in mitosis. We propose that Polη fulfills an important role in managing replicative stress at ALT telomeres, maintaining telomere recombination at tolerable levels and stimulating DNA synthesis by Polδ.


Assuntos
DNA Polimerase Dirigida por DNA/metabolismo , Proteômica/métodos , Homeostase do Telômero , Telômero/metabolismo , Biotinilação , DNA/biossíntese , DNA Polimerase III/metabolismo , Replicação do DNA , Células HeLa , Humanos , Mitose , Reparo de DNA por Recombinação
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