Attenuation of DNA polymerase β-dependent base excision repair and increased DMS-induced mutagenicity in aged mice
Attenuation of DNA polymerase β-dependent base excision repair and increased DMS-induced mutagenicity in aged mice
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DOI：
10.1016/s0027-5107(02)00003-9
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发表时间：
2002-03-20
影响因子：
2.3
通讯作者：
Heydari, AR
中科院分区：
文献类型：
--
作者：
Cabelof, DC;Raffoul, JJ;Heydari, AR
对衰老的生物学机制仍然知之甚少。我们认为，随着年龄的增长，DNA损伤和突变的增加是由于修复DNA损伤的能力降低。为了验证这一假设，我们测量了年轻（4个月大）和老年（24个月大）C57 BL/6小鼠组织中碱基切除修复（BER）途径体外修复DNA损伤的能力。我们发现，在所有测试的组织（脑、肝、脾和睾丸）中，修复损伤的能力随着年龄的增长而显著降低（50-75%; P < 0.01），并且随着年龄的增长而观察到的修复能力的降低与DNA聚合酶β（β-pol）酶活性、蛋白质和mRNA水平的降低相关。为了确定这种与年龄相关的BER下降的生物学相关性，我们测量了年轻和老年动物的自发和化学诱导的lacI突变频率。与以前的研究结果一致，我们观察到老年动物的自发突变频率增加了三倍。有趣的是，lacI突变频率在响应硫酸二甲酯（DMS）并没有显着增加，而在老年动物相同的曝光结果在突变频率增加了5倍。由于DMS诱导BER途径处理的DNA损伤，这表明DMS的致突变性随着年龄的增长而增加，这与BER能力随着年龄的增长而下降有关。BER通路不能修复随年龄积累的损伤，这可能为DNA损伤随年龄积累的成熟表型提供了一个机制解释。(C)2002 Elsevier Science B. V.保留所有权利。
The biological mechanisms responsible for aging remain poorly understood. We propose that increases in DNA damage and mutations that occur with age result from a reduced ability to repair DNA damage. To test this hypothesis, we have measured the ability to repair DNA damage in vitro by the base excision repair (BER) pathway in tissues of young (4-month-old) and old (24-month-old) C57BL/6 mice. We find in all tissues tested (brain, liver, spleen and testes), the ability to repair damage is significantly reduced (50-75%; P < 0.01) with age, and that the reduction in repair capacity seen with age correlates with decreased levels of DNA polymerase beta (beta-pol) enzymatic activity, protein and mRNA. To determine the biological relevance of this age-related decline in BER, we measured spontaneous and chemically induced lacI mutation frequency in young and old animals. In line with previous findings, we observed a three-fold increase in spontaneous mutation frequency in aged animals. Interestingly, lacI mutation frequency in response to dimethyl sulfate (DMS) does not significantly increase in young animals whereas identical exposure in aged animals results in a five-fold increase in mutation frequency. Because DMS induces DNA damage processed by the BER pathway, it is suggested that the increased mutagenicity of DMS with age is related to the decline in BER capacity that occurs with age. The inability of the BER pathway to repair damages that accumulate with age may provide a mechanistic explanation for the well-established phenotype of DNA damage accumulation with age. (C) 2002 Elsevier Science B.V. All rights reserved.