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1.
J Inherit Metab Dis ; 36(5): 773-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23138988

RESUMO

Hereditary tyrosinemia type I (HT1) is an autosomal recessive disease caused by a deficiency in human fumarylacetoacetate (FAA) hydrolase (FAH), which is the last enzyme in the catabolic pathway of tyrosine. Several reports suggest that intracellular accumulation of intermediates of tyrosine catabolism, such as FAA and succinylacetone (SA) is important for the pathogenesis in liver and kidney of HT1 patients. In this work, we examined the effect of FAA and SA on DNA glycosylases initiating base excision repair (BER), which is the most important pathway for removing mutagenic DNA base lesions. In vitro assays monitoring DNA glycosylase activities demonstrated that FAA but not SA inhibited base removal. In particular, the Neil1 and Neil2 DNA glycosylases were strongly inhibited, whereas inhibition of Nth1 and Ogg1 were less efficient. These DNA glycosylases initiate excision of a broad range of mutagenic oxidative base lesions. Further, FAA showed a modest inhibitory effect on the activity of the alkylbase DNA glycosylase Aag and no significant inhibition of the uracil DNA glycosylase Ung2. These data indicate that FAA inhibition of DNA glycosylases removing oxidative base lesions in HT1 patients may increase mutagenesis, suggesting an important mechanism for development of hepatocarcinoma and somatic mosaicism.


Assuntos
Acetoacetatos/farmacologia , Reparo do DNA , Tirosinemias/metabolismo , Tirosinemias/patologia , DNA/genética , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Desoxirribonuclease (Dímero de Pirimidina)/genética , Desoxirribonuclease (Dímero de Pirimidina)/metabolismo , Heptanoatos/farmacologia , Humanos , Mutagênese/genética , Tirosinemias/genética
2.
Gene ; 392(1-2): 283-90, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17331676

RESUMO

Sequence variability of RPCS (repetitive PuvII Ctenomys sequence), the major satellite DNA of octodontid Ctenomys rodents, was analysed in species belonging to three groups of species representing the two patterns of karyotypic evolution in the genus: stable and dynamic karyotypes among closely related species. The studied species represent the overall range of RPCS copy number (2000--6.6x10(6) copies per haploid genome) in the genus. RPCS sequence was characterised by PCR amplification of the genomic consensus sequence and cloned monomers. Our results suggest that RPCS genomic consensus sequence variability correlates with RPCS copy number stability and karyotypic stastis, but not with high or low RPCS copy number values. In contrast, the RPCS gcs shows a mutational profile that is similar across all analysed species. Our data suggest that an RPCS ancestral library of variants was maintained through the cladogenesis of the genus. There is also evidence pointing to the simultaneous contribution of processes of concerted evolution that resulted in a reduced representation of some ancestral variants and their partial replacement for new ones. In addition, analysis of distribution of the variability along the monomer suggests that subsequences of the RPCS are subject to some degree of constraint, probably driven by the recent replicative activity of RPCS in species with high copy number.


Assuntos
DNA Satélite/genética , Evolução Molecular , Roedores/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Amplificação de Genes , Biblioteca Gênica , Dados de Sequência Molecular , Filogenia , Homologia de Sequência
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