Ganguly T, Duker N J
Department of Pathology, Temple University School of Medicine, Philadelphia, PA 19140.
Mutat Res. 1992 Mar;275(2):87-96. doi: 10.1016/0921-8734(92)90012-e.
Werner's syndrome (WS) is an autosomal recessive disease marked by early symptoms of accelerated aging. There is evidence indicating accumulation of oxidized DNA bases to be a major factor in cellular aging. The first step of excision repair of such bases in human cells is their removal from DNA by glycosylases. 5-Hydroxymethyluracil (HMU)-DNA glycosylase excises HMU from DNA; another glycosylase removes many non-aromatic pyrimidine derivatives. Levels of glycosylases that excise oxidized pyrimidines from DNA were compared between confluent and proliferating populations of WS cells, age-matched controls, and young control cells. They were assayed by measurements of direct release of free bases from their respective DNA substrates. Specific activities of the glycosylase that releases various modified pyrimidines and of uracil-DNA glycosylase (which removes uracil from DNA) were essentially the same in all cell lines. Cell cycle variations of these enzymes also did not differ between WS and control cells. HMU-DNA glycosylase specific activity was reduced in WS cells. Reduction of HMU-DNA glycosylase has been described in senescent human WI-38 cells. Therefore, while neither WS nor senescent cells have overall deficiencies of DNA glycosylase activities, they both might have reduced excision of HMU from DNA. This indicates a possible role of HMU accumulation in the aging process.
沃纳综合征（WS）是一种常染色体隐性疾病，其特征为加速衰老的早期症状。有证据表明，氧化的DNA碱基积累是细胞衰老的主要因素。人类细胞中此类碱基切除修复的第一步是通过糖基化酶将它们从DNA中去除。5-羟甲基尿嘧啶（HMU）-DNA糖基化酶从DNA中切除HMU；另一种糖基化酶去除许多非芳香族嘧啶衍生物。在WS细胞的汇合群体和增殖群体、年龄匹配的对照细胞以及年轻对照细胞之间，比较了从DNA中切除氧化嘧啶的糖基化酶水平。通过测量各自DNA底物中游离碱基的直接释放来对它们进行测定。在所有细胞系中，释放各种修饰嘧啶的糖基化酶和尿嘧啶-DNA糖基化酶（从DNA中去除尿嘧啶）的比活性基本相同。这些酶的细胞周期变化在WS细胞和对照细胞之间也没有差异。WS细胞中HMU-DNA糖基化酶的比活性降低。在衰老的人类WI-38细胞中也描述了HMU-DNA糖基化酶的减少。因此，虽然WS细胞和衰老细胞都没有DNA糖基化酶活性的整体缺陷，但它们可能都减少了从DNA中切除HMU的能力。这表明HMU积累在衰老过程中可能发挥作用。
