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首页> 外文期刊>The Journal of Nutritional Biochemistry >Susceptibility to intestinal tumorigenesis in folate-deficient mice may be influenced by variation in one-carbon metabolism and DNA repair.
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Susceptibility to intestinal tumorigenesis in folate-deficient mice may be influenced by variation in one-carbon metabolism and DNA repair.

机译：叶酸缺乏小鼠肠道肿瘤发生的易感性可能受到一碳代谢和DNA修复变化的影响。

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摘要

Low dietary folate is associated with increased risk of colorectal cancer. In earlier work, we showed that folate deficiency induced intestinal tumors in BALB/c but not C57Bl/6 mice through increased dUTP incorporation into DNA with consequent DNA damage. To determine whether strain differences between one-carbon metabolism and DNA repair pathways could contribute to increased tumorigenesis in BALB/c mice, we measured amino acids and folate in the normal intestinal tissue of both strains fed a control diet or a folate-deficient diet. We also determined the expression of critical folate-metabolizing enzymes and several DNA repair enzymes. BALB/c mice had lower intestinal serine (major cellular one-carbon donor), methionine and total folate than C57Bl/6 mice under both dietary conditions. BALB/c mice had higher messenger RNA and protein levels of three folate-interconverting enzymes: trifunctional methyleneTHF (5,10-methylenetetrahydrofolate) dehydrogenase-methenylTHF cyclohydrolase-formylTHF (10-formyltetrahydrofolate) synthetase 1, bifunctional methyleneTHF dehydrogenase-methenylTHF cyclohydrolase and methylenetetrahydrofolate reductase. This pattern of expression could limit the availability of methyleneTHF for conversion of dUMP to dTMP. BALB/c mice also had higher levels of uracil DNA glycosylase 2 protein without an increase in the rate-limiting DNA polymerase beta enzyme, compared with C57Bl/6 mice. We conclude that BALB/c mice may be more prone to DNA damage through decreased amounts of one-carbon donors and the diversion of methyleneTHF away from the conversion of dUMP to dTMP. In addition, incomplete excision repair of uracil in DNA could lead to accumulation of toxic repair intermediates and promotion of tumorigenesis in this tumor-susceptible strain. All rights reserved, Elsevier.
机译：饮食中的叶酸含量低会增加患大肠癌的风险。在较早的工作中，我们表明叶酸缺乏可通过增加dUTP掺入DNA并导致DNA损伤而诱导BALB / c小鼠而非C57Bl / 6小鼠肠道肿瘤。为了确定一碳代谢和DNA修复途径之间的菌株差异是否可能导致BALB / c小鼠的肿瘤发生增加，我们测量了饲喂对照饮食或叶酸缺乏饮食的两种菌株的正常肠道组织中的氨基酸和叶酸。我们还确定了关键的叶酸代谢酶和几种DNA修复酶的表达。在两种饮食条件下，BALB / c小鼠的肠道丝氨酸（主要的细胞一碳供体），蛋氨酸和总叶酸含量均低于C57Bl / 6小鼠。 BALB / c小鼠具有三种叶酸互转换酶较高的信使RNA和蛋白质水平：三官能亚甲基THF（5,10-亚甲基四氢叶酸）脱氢酶-亚甲基THF环水解酶-甲酰基THF（10-甲酰基四氢叶酸）合成酶1，双官能亚甲基THF脱氢酶-亚甲基四氢叶酸再水解酶和亚甲基四氢水解酶。这种表达方式可能会限制亚甲基四氢呋喃用于dUMP转化为dTMP的可用性。与C57Bl / 6小鼠相比，BALB / c小鼠还具有更高水平的尿嘧啶DNA糖基化酶2蛋白，而没有增加限速DNA聚合酶β酶。我们得出的结论是，BALB / c小鼠可能通过减少一碳供体的量以及将甲基THF从dUMP转化为dTMP转移而更容易受到DNA损伤。另外，在该肿瘤易感菌株中，尿嘧啶在DNA中的不完全切除修复可能导致毒性修复中间体的积累并促进肿瘤发生。保留所有权利，Elsevier。

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