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The induction of mutations in mammalian cells exposed to cadmium has been associated with the oxidative stress triggered by the metal. There is increasing evidence that the mutagenic potential of Cd is not restricted to the induction of DNA lesions. Cd has been shown to inactivate several DNA repair enzymes. Here we show that exposure of human cells to sub-lethal concentrations of Cd leads to a time-...
Uracil appears in DNA as a result of cytosine deamination and by incorporation from the dUTP pool. As potentially mutagenic and deleterious for cell regulation, uracil must be removed from DNA. The major pathway of its repair is initiated by uracil-DNA glycosylases (UNG), ubiquitously found enzymes that hydrolyze the N-glycosidic bond of deoxyuridine in DNA. This review describes the current understanding...
Prominent lesions in DNA are abasic (AP) sites arising spontaneously or as intermediates during base excision repair. An AP site can form a Schiff base intermediate with primary amino groups of proteins. This intermediate can be stabilized by NaBH 4 treatment and, therefore, cross-linking of AP site-containing DNA (AP DNA) can be used as a tool in detecting proteins that interact with AP sites...
Aerobic respiration generates reactive oxygen species (ROS) as a by-product of cellular metabolism which can damage DNA. The complex nature of oxidative DNA damage requires actions of several repair pathways. Oxidized DNA bases are substrates for two overlapping pathways: base excision repair (BER) and nucleotide incision repair (NIR). In the BER pathway a DNA glycosylase cleaves the N-glycosylic...
Nucleotide excision repair operating throughout the mammalian genome plays a crucial role in the suppression of mutagenesis and carcinogenesis, which can arise from DNA lesions induced by a wide variety of genotoxic agents, such as ultraviolet light and chemical compounds. A key process of this DNA repair pathway, damage recognition, is accomplished through multiple steps including concerted actions...
Somatic mutations in mitochondrial DNA (mtDNA) are thought to play an important role in both aging and neurodegenerative diseases although their specific contributions remain a subject of intense debate. We analyzed somatic mutations in the mtDNA control regions in the liver of Wistar rats. The mutation rate was found to be high and increased with age from 5.3×10 −4 mutations per position...
Poly(ADP-ribose)polymerase 1 (PARP1), functioning as DNA nick-sensor, interacts with base excision repair (BER) DNA intermediates containing single-strand breaks. When bound to DNA breaks, PARP1 catalyzes synthesis of poly(ADP-ribose) covalently attached to itself and some nuclear proteins. Autopoly(ADP-ribosyl)ation of PARP1 facilitates its dissociation from DNA breaks and is considered as a factor...
To protect genomic integrity living cells that are continuously exposed to DNA-damaging insults are equipped with an efficient defence mechanism termed the DNA damage response. Its function is to eliminate DNA damage through DNA repair and to remove damaged cells by apoptosis. The DNA damage response has been investigated mainly in proliferating cells, in which the cell cycle machinery is integrated...
Covalent modifications of histones in chromatin play an important role in regulation of eukaryotic gene expression and DNA repair. Formation of double-strand breaks (DSBs) in DNA is followed by the rapid local phosphorylation of the C-terminal serine in the replacement histone H2AX in megabase chromatin domains around DSBs and formation of discrete nuclear foci called γH2AX foci. This epigenetic modification...
The recognition and subsequent repair of DNA damage are essential reactions for the maintenance of genome stability. A key general sensor of DNA lesions is xeroderma pigmentosum group C (XPC) protein, which recognizes a wide variety of helix-distorting DNA adducts arising from ultraviolet (UV) radiation, genotoxic chemicals and reactive metabolic byproducts. By detecting damaged DNA sites, this unique...
Fpg protein from Escherichia coli belongs to the class of DNA glycosylases/abasic site lyases excising several oxidatively damaged purines in the base excision repair pathway. In this review, we summarize the results of our studies of Fpg protein from E. coli, elucidating the intrinsic mechanism of recognition and excision of damaged bases in DNA.
Function of the eukaryotic genome depends on efficient and accurate replication of anti-parallel DNA strands. Eukaryotic DNA polymerases have different properties adapted to perform a wide spectrum of DNA transactions. Here we focus on major players in the bulk replication, DNA polymerases of the B-family. We review the organization of the replication fork in eukaryotes in a historical perspective,...
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