The eukaryotic nucleotide excision repair pathway

Costa, Ana Rita; Chiganças, Vanessa; Galhardo, Rodrigo S.; Carvalho, Helotônio; Menck, Carlos Frederico Martins

doi:10.1016/j.biochi.2003.10.017

Cited by 313 publications

(276 citation statements)

References 158 publications

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“…This complex is necessary for filling the gap left by the NER machinery. 15 The physical UV-induced association between p15 PAF and PCNA occurs through a PCNA-binding domain in p15 PAF , and has been described earlier. 16,17 To determine whether p15 PAF -mediated DNA repair requires association with PCNA and thus acts through PCNA, we sought to inhibit this association and evaluate the DNA repair efficiency.…”

Section: Resultsmentioning

confidence: 70%

“…PCNA is required for this process, as it acts as a processivity factor for both polymerases. 15 Interestingly, p15 PAF has been found to interact with both PCNA and Pol d 18 and therefore may contribute, as cofactor bound to PCNA, to the polymerase recruitment. Combined with the fact that reduced p15 PAF expression or inhibition of its binding to PCNA alters DNA repair, p15 PAF may be considered an essential cofactor in the DNA damage response.…”

Section: Discussionmentioning

confidence: 99%

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ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101/p15 PAF . We further show that the expressions of ATF3 and p15 PAF is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15 PAF compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15 PAF expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15 PAF expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15 PAF as novel gatekeepers of genomic integrity after UV exposure. Environmental genotoxic stress is one of the major causes of genomic instability. During such a stress, the maintenance of genomic integrity is of crucial importance to allow correct cellular function. The nucleotide excision repair (NER) machinery is responsible for recognition and incision of DNA lesions caused by ultraviolet (UV) irradiation and chemical agents. 1 Proliferating cell nuclear antigen (PCNA) is responsible for recruitment of Pold and, therefore, mediates DNA resynthesis within the site of the lesion. 1 The importance of such machinery is underscored by the numerous human syndromes, such as xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), caused by the mutation of genes involved in DNA repair. Such mutations compromise genomic integrity, and XP and TTD patients are highly photosensitive and prone to develop skin tumors of keratinocyte origin, such as basal and squamous cell carcinoma. Severe defects in the DNA repair mechanism thus impair the apoptotic pathway responsible for destruction of cells that bear the risk of becoming tumorigenic. The correct DNA damage response is therefore of great importance in the maintenance of a UV-inducible anticancer barrier that elicits growth arrest, repair or cell death.Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region leucine zipper (bZIP) family and may be strongly induced in a variety of tissues by different stress signals. 2 Several pathways are responsible for ATF3 induction, such as ATM and Nibrin 1, JNK and NF-kB, in a p53-dependent or -independent manner. 3-5 Induction of ATF3 often correlates with cellular damage, suggesting an important role during the cellular stress response. 6 We have recently reported that the alteration of Egr-1 expression during ...

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Section: Resultsmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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“…Both require multiple proteins that act in a multistep process: DNA damage recognition, DNA unwinding and incision, and finally repair synthesis and ligation. 14,15 The presence of UV-induced DNA lesions also activates members of the PI3 kinase family, ATR (ataxia telangiectasia and Rad3-related) and ATM (ataxia telangiectasia mutated). 16,17 ATR mediates the response to both UV-and IR-induced lesions as well as to stalled replication forks, whereas ATM is primarily responsible for the response to double-strand breaks (DSBs).…”

mentioning

confidence: 99%

The nucleotide excision repair pathway is required for UV-C-induced apoptosis in Caenorhabditis elegans

et al. 2007

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Ultraviolet (UV) radiation is a mutagen of major clinical importance in humans. UV-induced damage activates multiple signaling pathways, which initiate DNA repair, cell cycle arrest and apoptosis. To better understand these pathways, we studied the responses to UV-C light (254 nm) of germ cells in Caenorhabditis elegans. We found that UV activates the same cellular responses in worms as in mammalian cells. Both UV-induced apoptosis and cell cycle arrest were completely dependent on the p53 homolog CEP-1, the checkpoint proteins HUS-1 and CLK-2, and the checkpoint kinases CHK-2 and ATL-1 (the C. elegans homolog of ataxia telangiectasia and Rad3-related); ATM-1 (ataxia telangiectasia mutated-1) was also required, but only at low irradiation doses. Importantly, mutation of genes encoding nucleotide excision repair pathway components severely disrupted both apoptosis and cell cycle arrest, suggesting that these genes not only participate in repair, but also signal the presence of damage to downstream components of the UV response pathway that we delineate here. Our study suggests that whereas DNA damage response pathways are conserved in metazoans in their general outline, there is significant evolution in the relative importance of individual checkpoint genes in the response to specific types of DNA damage.

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“…por mecanismos de reparo do DNA (Costa et al, 2003). O fotoproduto 6-4PP é praticamente todo removido em 6 h, enquanto que 50% de CPD ainda persiste 24 h após a irradiação com luz UV (Kobayashi et al, 2001).…”

Section: Luz Uv E Consequências Dos Fotoprodutosunclassified

Resposta a danos no DNA após exposição à luz ultravioleta: apagando o fogo antes do incêndio celular

Lima¹

2015

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Resumo. O DNA é uma molécula reativa e estima-se que mais de 20 mil lesões no DNA sejam induzidas de maneira endógena por dia por célula, além de outras induzidas por agentes exógenos como a luz ultravioleta, resultando em bloqueio físico das maquinarias de replicação e transcrição do DNA Em resposta a lesões no DNA, células ativam respostas que promovem regulação do ciclo celular e reparo do DNA, evitando catásfrofes durante a replicação ou na mitose. Caso a quantidade de danos ultrapasse a capacidade de reparo, as células podem induzir morte celular como último recurso. A importância das respostas ao dano no DNA é exemplificada por síndromes humanas, com fenótipo de envelhecimento precoce ou aumento de risco de câncer, e seu estudo poderá contribuir para o entendimento da tumorigênese e desenvolvimento de melhores terapias. A reatividade do DNA e necessidade de reparoInicialmente, o DNA era percebido como uma macromolécula altamente estável, porém somente algum tempo depois que a estrutura da dupla-hélice foi desvendada por Watson e Crick é que foi compreendida a sua instabilidade natural, devido à sua estrutura química e reatividade com numerosa quantidade de agentes químicos e físicos. Curiosamente, muito antes da constatação de que DNA era o material hereditário das células, em 1944, já era conhecido que agentes ambientais como raios-X induziam mutações (Muller, 1927) e que células tinham habilidade inata de se recuperarem de irradiação com luz ultravioleta (UV), mesmo sem saber exatamente que tipo de dano era induzido em células (Hollander e Claus, 1936). O primeiro mecanismo de recuperação celular -a fotorreativação -foi descrito em 1949 (Kelner, 1949), mas foi na década de 60 que foi desvendada a natureza da lesão no DNA provocada por luz UV e o mecanismo independente de luz -o reparo por excisão de nucleotídeos. Ao longo do tempo, outros tipos de danos no DNA, além dos induzidos por radiações, foram descritos reafirmando a alta reatividade da molécula de DNA e a necessidade de correção das lesões. A figura 1 resume trabalhos de destaque que contribuíram para o entendimento da resposta celular ao dano no DNA através de uma linha do tempo, adaptada da revisão de Ljungman, 2010.Danos no DNA são alterações químicas da dupla-hé-lice que desafiam constantemente a estabilidade genômica, já que podem comprometer o metabolismo do DNA (replicação e transcrição) e resultarem em mutações pontuais, durante a fase S, ou em aberrações cromossômicas quando existem quebras no DNA. Assim, desempenham importante papel nos processos biológicos de tumorigênese e envelhecimento (Friedberg, 2003; Menck e Munford, 2014). Hoje

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The eukaryotic nucleotide excision repair pathway

Cited by 313 publications

References 158 publications

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

The nucleotide excision repair pathway is required for UV-C-induced apoptosis in Caenorhabditis elegans

Resposta a danos no DNA após exposição à luz ultravioleta: apagando o fogo antes do incêndio celular

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