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Even though polymerase, B   is involved in cellular repair synthesis, it is thought to act mainly on short gaps generated during base excision repair. Besides a direct interaction with repair enzymes, lead and cadmium ions might also interfere with calciumregulated processes involved in the regulation of DNA replication and repair.Even though manifold interactions between lead and calcium concerning uptake, calcium homeostasis and substitution of lead, their potential role in repair inhibition has yet to be elucidated.Especially for lead, the interference with DNA repair processes seems to be the main mechanism of genotoxicity.This might help to explain the conflicting results of epidemiological studies with regard to the clastogenic and carcinogenic potential of lead compounds.Since the removal of these DNA lesions is mediated by the nucleotide excision repair system, which is generally acting on bulky DNA damage, it may be expected that lead and cadmium also increase the genotoxicity when combined with other DNA damaging agents.DNA repair synthesis in human fibroblasts requires DNA polymerase. Biochim Biophys Acta. Potentiation of bleomycin lethality by anticalmodulin drugs: a role for calmodulin in DNA repair.Neurotoxicology. Inhibitory effect of cadmium and mercury ions on induction of the adaptive response in Eschericia coli. Environmental Health Perspectives The genomic integrity of all living organisms is constantly jeopardized by physical and chemical agents that damage the DNA.To overcome the deleterious effects of DNA lesions, nature evolved a number of complex multiprotein repair processes with broad, <a href="http://www.targetmol.com/compound/Diclofenac">buy Diclofenac</a> partially overlapping substrate specificity.In marked contrast, cells may use very simple repair systems, referred to as direct DNA damage reversal, that rely on a single protein, remove lesions in a basically errorfree manner, show high substrate specificity, and do not involve incision of the sugarphosphate backbone or base excision.Replication of damaged DNA can cause mutations, which ultimately can lead to cancer, while DNA lesions that obstruct replication and transcription can lead to cellular senescence or apoptosis, which are believed to contribute to diseases of aging. In contrast to other biomolecules, DNA cannot be replaced, only repaired.In addition to these complex, often errorprone, genome maintenance systems, nature has evolved single enzyme mechanisms that can repair lesions without incision of the DNA sugarphosphate backbone or base excision.The relative simplicity of these repair mechanisms, referred to as direct damage reversal, predicts essentially errorfree repair, with, however, a very narrow substrate range as a tradeoff.This concise review deals with the two main types of direct DNA damage reversal systems: repair UV lightinduced photolesions by spore photoproduct lyases and photolyases.Biologically important lesions formed in doublestranded DNA. In addition, phosphodiester groups in DNA might become methylated.Although alkylated bases can be removed by multistep excision repair processes, several lesions are also subject to effective and highly specific direct repair mechanisms.Methylated MGMT cannot be reused and disappears rapidly from cells by ubiquitinmediated degradation. Several polymorphisms are known for the MGMT gene in the human population, some affecting protein activity or expression level, but associations with cancer risk are not consistent. Some tumorderived cell lines are very sensitive to alkylating agents.Transgenic mice carrying the human MGMT gene behind a bovine cytokine promoter, which expresses selectively in the epidermis, exhibited a significantly lower tumor incidence in a twostage topical tumor induction protocol compared to nontransgenic animals.

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