Uracil in DNA: consequences for carcinogenesis and chemotherapy.
Uracil in DNA: consequences for carcinogenesis and chemotherapy.
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DOI：
10.1016/j.bcp.2008.05.019
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发表时间：
2008-09-15
影响因子：
5.8
通讯作者：
Wyatt, Michael D.
中科院分区：
文献类型：
--
作者：
Berger, Sondra H.;Pittman, Douglas L.;Wyatt, Michael D.
胸苷酸酯（TMP）的合成涉及叶酸代谢和嘧啶生物合成两个关键代谢途径的融合。胸苷酸是由脱氧尿苷酸（dUMP）使用N5， N10亚甲基四氢叶酸形成的。从预防到化疗，dUMP、TMP和叶酸之间的代谢关系一直是癌症研究的主题。胸苷酸应激是由叶酸营养缺乏、叶酸代谢缺陷以及抗叶酸和氟嘧啶化疗引起的。这两类化学疗法仍然是治疗实体瘤的主要方法。由于dUMP和TMP之间的密切关系，胸苷酸应激与尿嘧啶进入DNA的增加有关。基因组尿嘧啶被尿嘧啶DNA糖基酶的碱基切除修复（BER）去除。不幸的是，胸腺苷酸应激时BER明显有问题。由于BER需要DNA再合成步骤，dUTP升高会导致基因组尿嘧啶的重新引入。如果不进行修复，BER链断裂中间体是致裂性的。因此，胸苷酸应激期间的BER似乎会导致基因组不稳定，但也可能有助于抗叶酸盐和氟嘧啶的作用机制。然而，BER及其组分在胸苷酸胁迫中的确切作用尚不清楚。特别是，BER和下游事件之间的联系仍然不明确，包括损伤信号通路和同源重组（HR）。越来越多的证据表明，HR对持续的BER链断裂中间体有反应，DNA损伤信号通路介导了BER和HR之间的串扰。研究BER、HR和损伤信号之间的串扰可能会为几十年来的研究提供线索，并为开发新的化学预防和化学治疗方法提供见解。
The synthesis of thymidylate (TMP) occupies a convergence of two critical metabolic pathways: folate metabolism and pyrimidine biosynthesis. Thymidylate is formed from deoxyuridylate (dUMP) using N5, N10 methylene tetrahydrofolate. The metabolic relationship between dUMP, TMP, and folate has been the subject of cancer research from prevention to chemotherapy. Thymidylate stress is induced by nutritional deficiency of folic acid, defects in folate metabolism, and by antifolate and fluoropyrimidine chemotherapeutics. Both classes of chemotherapeutics remain mainstay treatments against solid tumors. Because of the close relationship between dUMP and TMP, thymidylate stress is associated with increased incorporation of uracil into DNA. Genomic uracil is removed by uracil DNA glycosylases of base excision repair (BER). Unfortunately, BER is apparently problematic during thymidylate stress. Because BER requires a DNA resynthesis step, elevated dUTP causes reintroduction of genomic uracil. BER strand break intermediates are clastogenic if not repaired. Thus, BER during thymidylate stress appears to cause genome instability, yet might also contribute to the mechanism of action for antifolates and fluoropyrimidines. However, the precise roles of BER and its components during thymidylate stress remain unclear. In particular, links between BER and downstream events remain poorly defined, including damage signaling pathways and homologous recombination (HR). Evidence is growing that HR responds to persistent BER strand break intermediates and DNA damage signaling pathways mediate cross talk between BER and HR. Examination of crosstalk among BER, HR, and damage signaling may shed light on decades of investigation and provide insight for development of novel chemopreventive and chemotherapeutic approaches.
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DOI：
10.1016/j.mrgentox.2006.10.001
发表时间：
2007-01-10
影响因子：
1.9
作者：
Crott, Jimmy W.;Liu, Zhenhua;Mason, Joel B.
通讯作者：
Mason, Joel B.
影响因子：
11.4
作者：
GADSDEN, MH;MCINTOSH, EM;HAYNES, RH
通讯作者：
HAYNES, RH
DOI：
10.1073/pnas.2334585100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Cortellino, S;Turner, D;Bellacosa, A
通讯作者：
Bellacosa, A
影响因子：
4.7
作者：
Andersen, S;Heine, T;Nilsen, H
通讯作者：
Nilsen, H
DOI：
10.1073/pnas.94.7.3290
发表时间：
1997-04-01
影响因子：
11.1
作者：
Blount, BC;Mack, MM;Ames, BN
通讯作者：
Ames, BN