XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility.
XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility.
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DOI：
10.1093/nar/gkr280
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发表时间：
2011-10
影响因子：
14.9
通讯作者：
Wilson DM 3rd
中科院分区：
文献类型：
--
作者：
McNeill DR;Lin PC;Miller MG;Pistell PJ;de Souza-Pinto NC;Fishbein KW;Spencer RG;Liu Y;Pettan-Brewer C;Ladiges WC;Wilson DM 3rd
氧化性DNA损伤在疾病发展和衰老过程中发挥作用。在DNA氧化损伤，特别是单链断裂的修复过程中，一个重要的参与者是支架蛋白XRCC1。研究了XRCC1杂合（HZ）小鼠的一系列时间和生物学老化参数。HZ和野生型（WT） C57BL/6小鼠的中位寿命相似，为~26个月，最大寿命几乎相同，为~37个月。然而，许多HZ动物（92只中的7只）显示出腹部器官破裂的倾向，这可能源于发育异常，因为XRCC1在内胚层和中胚层形成中起着重要作用。对于其他评估的终点——体重、脂肪组成、血液化学、主要器官状况、组织和相关细胞类型、行为、脑容量和功能、染色体和端粒完整性——hz小鼠总体上表现为正常表型。用烷基化剂偶氮氧甲烷处理动物导致HZ小鼠的肝毒性和结肠癌前病变发生率增加。我们的研究表明，在没有环境挑战的情况下，哺乳动物的XRCC1单倍性不足对时间寿命和许多关键的衰老生物学标志物影响不大，但可能对正常动物发育产生不利影响，或增加相关基因毒性暴露的疾病易感性。
Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of ~26 months and a nearly identical maximal life expectancy of ~37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated—weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity—HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure.
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Berquist BR;Singh DK;Fan J;Kim D;Gillenwater E;Kulkarni A;Bohr VA;Ackerman EJ;Tomkinson AE;Wilson DM 3rd
通讯作者：
Wilson DM 3rd
影响因子：
30.8
作者：
Date, H;Onodera, O;Tsuji, S
通讯作者：
Tsuji, S
影响因子：
--
作者：
Dutra, Ana V. C.;Lin, Hsiu-Fen;Grewal, Raji P.
通讯作者：
Grewal, Raji P.
影响因子：
14.9
作者：
Kulkarni, Avanti;McNeill, Daniel R.;Wilson, David M., III
通讯作者：
Wilson, David M., III