Abstract
The accumulation of modified or damaged bases in genomic DNA is a major threat for the alteration of genetic information as a result of mutagenesis or even for programmed cell death. It has been established that such damaged bases in genomic DNA arise from two independent pathways: one is a consequence of the direct modification of the normal bases in the DNA and the other is that of the incorporation of modified nucleotides generated in resident nucleotide pools. 8-oxo-dGTP is one of the major causes for spontaneous mutagenesis, because 8-oxo-dGTP is formed by the spontaneous oxidation of dGTP in the nucleotide pool, and it is incorporated into the nascent strand opposite adenine as well as cytosine in the template strand during DNA replication. We have demonstrated that 8-oxo-dGTP is hydrolyzed by MutT family proteins from prokaryotes to humans, and, as a result organisms maintained a low spontaneous mutation rate. Recently, genome projects revealed the existence of many MutT-like proteins with different substrate specificities, and a structure-based approach identified another novel enzyme, ITPase which hydrolyzes deaminated purine nucleoside triphosphates, such as (d)ITP and (d)XTP. In Escherichia coli, a mutant of rdgB gene coding ITPase protein is viable but it shows synthetic lethality with recA or recBC mutation. It is likely that dITP or dXTP accumulated in the nucleotide pools exhibits cytotoxicity in the absence of recombination repair.
I will review the molecular pathophysiology caused by deficiency in human or mouse MutT homologs as well as ITPase homologs.
