Papel da proteína de reparo XPC na regulação das proteínas de reparo APE1, OGG1 e PARP-1 em células humanas e de camundongos
studies using UV as a source of DNA damage. However, even though unrepaired UV-induced DNA damages are related to mutagenesis, cell death and tumorigenesis, they do not explain phenotypes such as neurodegeneration and internal tumors observed in patients with syndromes like Xeroderma Pigmentosum...
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Formato: | doctoralThesis |
Idioma: | por |
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Universidade Federal do Rio Grande do Norte
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Endereço do item: | https://repositorio.ufrn.br/jspui/handle/123456789/12573 |
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Resumo: | studies using UV as a source of DNA damage. However, even though unrepaired
UV-induced DNA damages are related to mutagenesis, cell death and tumorigenesis,
they do not explain phenotypes such as neurodegeneration and internal tumors
observed in patients with syndromes like Xeroderma Pigmentosum (XP) and
Cockayne Syndrome (CS) that are associated with NER deficiency. Recent
evidences point to a role of NER in the repair of 8-oxodG, a typical substrate of Base
Excision Repair (BER). Since deficiencies in BER result in genomic instability,
neurodegenerative diseases and cancer, it was investigated in this research the
impact of XPC deficiency on BER functions in human cells. It was analyzed both the
expression and the cellular localization of APE1, OGG1 e PARP-1, the mainly BER
enzymes, in different NER-deficient human fibroblasts. The endogenous levels of
these enzymes are reduced in XPC deficient cells. Surprisingly, XP-C fibroblasts
were more resistant to oxidative agents than the other NER deficient fibroblasts,
despite presenting the highest of 8-oxodG. Furthermore, subtle changes in the
nuclear and mitochondrial localization of APE1 were detected in XP-C fibroblasts. To
confirm the impact of XPC deficiency in the regulation of APE1 and OGG1
expression and activity, we constructed a XPC-complemented cell line. Although the
XPC complementation was only partial, we found that XPC-complemented cells
presented increased levels of OGG1 than XPC-deficient cells. The extracts from
XPC-complemented cells also presented an elevated OGG1 enzimatic activity.
However, it was not observed changes in APE1 expression and activity in the XPCcomplemented
cells. In addition, we found that full-length APE1 (37 kDa) and OGG1-
α are in the mitochondria of XPC-deficient fibroblasts and XPC-complemented
fibroblasts before and after induction of oxidative stress. On the other hand, the
expression of APE1 and PARP-1 are not altered in brain and liver of XPC knockout
mice. However, XPC deficiency changed the APE1 localization in hypoccampus and
hypothalamus. We also observed a physical interaction between XPC and APE1
proteins in human cells. In conclusion, the data suggest that XPC protein has a role
in the regulation of OGG1 expression and activity in human cells and is involved
mainly in the regulation of APE1 localization in mice. Aditionally, the response of
NER deficient cells under oxidative stress may not be only associated to the NER
deficiency per se, but it may include the new functions of NER enzymes in regulation
of expression and cell localization of BER proteins |
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