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

加速衰老 Mouso 氧化 DNA 损伤修复系统分析

• 批准号: 11680819
• 负责人: MORI Masayuki
• 金额: $ 2.37万
• 依托单位: Shinshu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680819/
• 关键词: accelerated senescence; oxidative stress; SAM; 8-oxoguanine; OGG1; SAM; 8-OHdG

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.

衰老加速小鼠（SAMP）品系表现出加速衰老和短寿命的遗传特征，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诱变前氧化碱基之一，被怀疑在生物体衰老中发挥着至关重要的作用。哺乳动物 8-氧鸟嘌呤 DNA 糖基化酶 (OGG1) 被认为在体内去除 8-氧鸟嘌呤加合物方面发挥着重要作用。我们评估了 8-氧代鸟嘌呤和 OGG1 以及加速 SAMP 小鼠衰老和缩短寿命的可能影响。对 SAM 菌株的 Ogg1 基因的检查表明，除 SAMR3 外，所有 SAM 菌株均在 OGG1 中保留 R336H 取代。此外，所有九个 SAMP 菌株（但五个 SAMR 菌株均无）具有 R304W 取代。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破坏，但活性保持正常。我们还发现，与正常小鼠相比，SAMP1 的肝核 DNA 8-氧鸟嘌呤水平保持了 1.5 至 1.9 倍的增加。直到至少 12 个月大。然而，一项利用源自 SAMP1 小鼠的两个杂交后代的遗传关联研究表明，突变的 Ogg1 基因本身并不是 SAMP1 加速衰老和寿命缩短的原因。这些数据并不排除高 8-氧鸟嘌呤水平的保留与 SAMP1 小鼠加速衰老和寿命短有关的可能性。利用 SAMP1 小鼠的进一步研究可能会阐明 8-氧代鸟嘌呤在衰老中的可能含义。

项目成果

Yanming Xing: "Transmission of mouse senile amyloidosis"Laboratory Investigation. (印刷中).

邢彦明：“小鼠老年淀粉样变性的传播”实验室调查（出版中）。

Masayuki Mori: "Deletion in the beige gene of the beige rat owing to recombination between LINEls"Mammalian Genome. 10(7). 622-625 (1999)

Masayuki Mori：“由于 LINEls 之间的重组，导致米色大鼠的米色基因缺失”哺乳动物基因组。

ZhanJun Guo: "Genetic analysis of lifespan in hybrid progeny derived from the SAMP1 mouse strain with accelerated senescence"Mechanisms of Ageing & Development. 118(1-2). 435-444 (2000)

郭占军：“加速衰老的SAMP1小鼠品系杂交后代寿命的基因分析”衰老机制

Yanming Xing: "Transmission of mouse senile amyloidosis"Laboratory Investigation. (in press).

邢彦明：“小鼠老年淀粉样变性的传播途径”实验室调查。

Masayuki Mori: "Spontaneous loss-of-function mutations of the 8-oxoguanine DNA glycosylase gene in mice and exploration of the possible implication of the gene in senescence"Free Radical Biology & Medicine. (印刷中).

Masayuki Mori：“小鼠 8-氧代鸟嘌呤 DNA 糖基化酶基因的自发功能丧失突变以及该基因在衰老中的可能含义的探索”《自由基生物学与医学》（正在出版）。