DNA-DAMAGE IN FOLATE-DEFICIENCY
DNA-DAMAGE IN FOLATE-DEFICIENCY
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DOI：
10.1016/s0950-3536(05)80216-1
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发表时间：
1995-09-01
期刊：
影响因子：
--
通讯作者：
AMES, BN
中科院分区：
文献类型：
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作者：
BLOUNT, BC;AMES, BN
叶酸缺乏会破坏染色体，并与人类癌症风险增加有关（Blount，1994; Glynn和Albanes，1994）。缺乏叶酸的上皮组织发生肿瘤转化的风险增加（巴特沃思，1993），这可能是由于叶酸在DNA合成、修复和甲基化中发挥的作用（Krumdieck，1983）。叶酸缺乏可通过尿嘧啶错误掺入导致染色体断裂或DNA甲基化降低而导致舞蹈病风险增加（赫伯特，1986）。尿嘧啶错误掺入/修复和低甲基化不是相互排斥的机制，两者都可能很重要。叶酸缺乏诱导的低甲基化在癌发生中的作用最近已被综述（Mason，1995）。本章将重点讨论尿嘧啶错误掺入和修复在诱导染色体断裂和癌症中的潜在作用，尿嘧啶错误掺入DNA及其随后的切除修复是叶酸缺乏诱导人类染色体断裂的一种可能机制（Goulian et al，1980 b; Reidy，1988; MacGregor et al，1990; Wickramasinghe and Fida，1994）。叶酸缺乏减少了胸苷酸脱氢酶介导的脱氧尿苷酸甲基化为胸苷酸（马修斯等人，1990）。随后的核苷酸不平衡增加了尿嘧啶错误掺入DNA的频率（Goulian et al，1980 b）。同时去除和修复相对链上的两个相邻尿嘧啶残基可导致双链DNA断裂（Dianov et al，1991）和遗传稳定性降低（图1）。本文回顾的结果表明，叶酸缺乏导致尿嘧啶错误掺入和显着增加染色体断裂的微核细胞测量。计算结果解释了观察到的尿嘧啶错误掺入水平如何导致染色体断裂（Blount，1994）。未修复的双链DNA断裂会降低遗传稳定性，从而增加癌症风险（Rosin和Ochs，1986;温伯格，1988）。
Folic acid deficiency breaks chromosomes and is associated with increased cancer risk in humans (Blount, 1994; Glynn and Albanes, 1994). Folate-deficient epithelial tissues are at increased risk of neoplastic transformation (Butterworth, 1993), probably due to the role that folate plays in DNA synthesis, repair and methylation (Krumdieck, 1983). Folate deficiency could cause increased risk of dancer by breaking chromosomes due to uracil misincorporation or by decreasing DNA methylation (Herbert, 1986). Uracil misincorporation/repair and hypomethylation are not mutually exclusive mechanisms and both could be important. The role of folate deficiency-induced hypomethylation in carcinogenesis has been reviewed recently (Mason, 1995). This chapter will focus on the potential role of uracil misincorporation and repair for inducing chromosome breaks and cancer.Uracil misincorporation into DNA and its subsequent excision repair is a plausible mechanism for folate deficiency-induced chromosome breaks in humans (Goulian et al, 1980b; Reidy, 1988; MacGregor et al, 1990; Wickramasinghe and Fida, 1994). Folate deficiency reduces thymidylate synthase-mediated methylation of deoxyuridylate to thymidylate (Matthews et al, 1990). The ensuing nucleotide imbalance increases the frequency of uracil misincorporation into DNA (Goulian et al, 1980b). Simultaneous removal and repair of two adjacent uracil residues on opposite strands can result in a double-strand DNA break (Dianov et al, 1991) and decreased genetic stability (Figure 1). Results reviewed here indicate that folate deficiency in humans causes uracil misincorporation and significant increases in chromosome breaks as measured by micronucleated cells. A calculation is presented to explain how the levels of uracil misincorporation observed may cause chromosome breaks (Blount, 1994). Unrepaired double-strand DNA breaks decrease genetic stability and therefore increase cancer risk (Rosin and Ochs, 1986; Weinberg, 1988).