Analysis of repair systems for oxidative DNA damage in Senescence-Accelerated Mouso

衰老加速小鼠倾向（SAMP）菌株表现出衰老加速和寿命缩短的遗传特征，因此是阐明生物体衰老过程机制的有用动物模型。8-氧鸟嘌呤是体内主要的致突变前氧化碱基之一，被怀疑在机体衰老中起着至关重要的作用。哺乳动物8-氧鸟嘌呤DNA糖基化酶（OGG1）被认为在体内去除8-氧鸟嘌呤加合物中起主要作用。我们已经评估了8-氧鸟嘌呤和OGG1与SAMP小鼠加速衰老和缩短寿命的可能含义。对SAM菌株Ogg1基因的检测表明，除SAMR3外，所有SAM菌株的Ogg1均含有R336H取代。此外，9株SAMP均有R304W替代，而5株SAMR均无R304W替代。我们发现R304W突变导致OGG1活性完全丧失，而R336H突变导致酶的核定位中断，尽管活性保持正常。我们还发现，与正常小鼠相比，SAMP1的肝核DNA中8-氧鸟嘌呤水平增加了1.5至1.9倍。直到至少12个月大。然而，一项利用来自SAMP1小鼠的两个杂交后代进行的遗传关联研究表明，突变的Ogg1基因本身并不是SAMP1加速衰老和缩短寿命的原因。这些数据并不排除8-氧鸟嘌呤高水平的保留与SAMP1小鼠衰老加速和寿命缩短有关的可能性。利用SAMP1小鼠的进一步研究可能阐明8-氧鸟嘌呤在衰老中的可能作用。

Senescence-Accelerated Mouse Prone (SAMP) strains, show accelerated senescence coupled with a short lifespan as a genetic trait, and hence are a useful animal model to elucidate the mechanisms involved in organismal senescence process. 8-Oxoguanine is one of the major premutagenic oxidative base legions in vivo and is suspected to play a crucial role in organismal senescence. Mammalian 8-oxoguanine DNA glycosylase (OGG1) is thought to play a major role in the removal of 8-oxoguanine adducts in vivo. We have assessed the possible implication of 8-oxoguanine and OGG1 and accelerated senescence and short lifespan of SAMP mice. Examination of the Ogg1 gene of SAM strains have revealed that all SAM strains, except for SAMR3, hold R336H substitution in the OGG1. In addition, all nine SAMP strains, but none of the five SAMR strains, had the R304W substitution. We have revealed that R304W mutation caused a complete loss of OGG1 activity, while the R336H mutation led to disruption of nuclear localization of the enzyme although the activity remained normal. We have also revealed that 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 association study utilizing two hybrid progenies originated from SAMP1 mice, however, indicated that the mutant Ogg1 gene per se is not responsible for the accelerated senescence and short lifespan of SAMP1. These data do not preclude the possibility that retention of the high 8-oxoguanine level is associated with accelerated senescence and short lifespan of SAMP1 mice. Further study utilizing SAMP1 mice might elucidate the possible implication of 8-oxoguanine in senescence.