O papel da via de reparo por excisão de nucleotídeos na resposta celular ao estresse oxidativo e o estudo de alterações neuronais in vitro associadas a síndrome de Cockayne
In oxidative stress response, the base excision repair (BER) is considered the major pathway for repair of oxidative lesions. However, an increasing number of studies have indicated the role of nucleotide excision (NER) in the repair of these lesions. In addition, some NER factors had functions...
Na minha lista:
| Autor principal: | |
|---|---|
| Outros Autores: | |
| Formato: | doctoralThesis |
| Idioma: | por |
| Publicado em: |
Brasil
|
| Assuntos: | |
| Endereço do item: | https://repositorio.ufrn.br/jspui/handle/123456789/22713 |
| Tags: |
Adicionar Tag
Sem tags, seja o primeiro a adicionar uma tag!
|
| Resumo: | In oxidative stress response, the base excision repair (BER) is
considered the major pathway for repair of oxidative lesions. However, an
increasing number of studies have indicated the role of nucleotide excision
(NER) in the repair of these lesions. In addition, some NER factors had
functions beyond the role in repair already described and it is important to
search for new molecular functions that can be associated to the classical
phenotypes of the syndromes caused by mutations in NER genes: Xeroderma
pigmentosum complementation group A, caused by mutations in XPA and
Cockayne syndrome, caused by mutations in CSB. In this context, XPA
(XP12RO) or CSB (CS1AN) deficient cells were submitted to oxidative stress
induced by Hydrogen peroxide (H2O2) and the results indicated that both cell
lines showed sensitivity to this agent. Furthermore, the transcriptome of
XP12RO cells revealed the downregulation of genes that play a role in DNA
damage response and promote cell survival in response to oxidative stress. In
this scenario, the results indicated that XPA regulates the expression of genes
that play a key role in DNA damage response and promote survival in response
to stress (EGR1, GADD45A, GADD45B and XPC). On the other hand, the
transcriptome analysis of CS1AN cells showed the downregulation of genes
that play a key role in biological processes such as transcription, mRNA
processing, protein degradation by the ubiquitin–proteasome pathway
proteolysis or cellular respiration, indicating a possible role for CSB protein in
the regulation of these processes, in response to oxidative stress. In adittion,
given the neurodegeneration phenotype associated to Cockayne syndrome,
neural progenitor cells (NPCs) and neurons derived from CSB deficient induced
pluripotent stem cells (iPSCs) were used as cellular models to analyse neuronal
changes in vitro. The results showed that, as observed in fibroblasts CS1AN,
NPCs also presented sensitivity to oxidizing agents. Furthermore, as indicated
in the transcriptome data from CS1AN fibroblasts, given the downregulation of
genes that play a pivotal role in cellular respiration, the analysis of oxygen
consumption rates in CSB deficient neurons also indicated a mitochondrial
dysfunction characterized by the decrease in oxygen consumption basal rate
and a lower maximum respiratory and reserve capacities, suggesting that the
lack of functional CSB leads to a mitochondrial dysfunction in both cellular
models used in this study. |
|---|