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

加速衰老小鼠倾向(SAMP)品系表现出加速衰老和短寿命相结合的遗传特征，因此是阐明生物衰老过程中涉及机制的有用的动物模型。8-氧鸟嘌呤是体内主要的诱变前氧化碱基军团之一，被认为在生物体衰老中起着至关重要的作用。哺乳动物8-氧鸟嘌呤DNA糖基酶(OGG1)被认为在体内8-氧鸟嘌呤加合物的去除过程中起着重要作用。我们评估了8-氧鸟嘌呤和OGG1在加速SAMP小鼠衰老和缩短寿命方面的可能意义。对SAM株Ogg1基因的检测表明，除SAMR3外，所有SAM株在OGG1中都存在R336H替换。此外，所有9个SAMP菌株，但5个SAMR菌株中没有一个存在R304W替换。我们发现，R304W突变导致OGG1活性完全丧失，而R336H突变导致该酶的核定位中断，但活性保持正常。我们还发现，SAMP1组小鼠肝细胞核DNA中8-氧鸟嘌呤的含量比正常小鼠高1.5~1.9倍。直到至少12个月大。然而，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衰老加速和寿命短的原因。这些数据不排除保留高水平的8-氧鸟嘌呤与SAMP1小鼠衰老加速和寿命短有关的可能性。利用SAMP1小鼠进行的进一步研究可能会阐明8-氧鸟嘌呤在衰老过程中的可能意义。

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.