Spontaneous loss-of-function mutations of the 8-oxoguanine DNA glycosylasegene in mice and exploration of the possible implication of the gene in senescence

8-Oxoguanine is one of the major premutagenic oxidative base legions in viv o and is suspected to play a crucial role in various pathophysiological pro cesses, such as cancer and aging. Mammalian 8-oxoguanine DNA glycosylase (O OG1) is thought to play a major role in the removal of 8-oxoguanine adducts in vivo. We have identified several inbred mouse strains with a spontaneou s mutation, OGG1-R336H or double mutations, OGC1-R304W/R336H. R304W mutatio n caused a complete loss of OGG1 activity, while the R336H mutation led to disruption of nuclear localization of the enzyme although the activity rema ined normal. Among the double mutants was SAMP1, which exhibits accelerated senescence and short lifespan. We assessed the possible implication of the mutant OGG1 and 8-oxoguanine in aging utilizing SAMP1 mice. SAMP1 retained 1.5- to 1.9-fold increase in 8-oxoguanine level of hepatic nuclear DNA as compared with normal mice, until at least 12 months of age. A genetic assoc iation study, however, indicated that the mutant Ogg1 gene per se is not re sponsible for the accelerated senescence and short lifespan of SAMP1. Mutan t OGG1 may be associated with pathologic conditions in other mouse strains. (C) 2001 Elsevier Science Inc.