Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase
Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase
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DOI：
10.1515/cclm.2007.355
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发表时间：
2007-01-01
影响因子：
6.8
通讯作者：
Stover, Patrick J.
中科院分区：
文献类型：
--
作者：
Anderson, Donald D.;Woeller, Collynn F.;Stover, Patrick J.
背景资料：叶酸介导的一碳代谢障碍与病理和发育异常有关，包括心血管疾病、癌症、神经系统疾病和神经管缺陷。详细说明叶酸和一碳代谢在这些疾病中的作用的机制仍有待建立。叶酸缺乏损害叶酸依赖性胸苷酸生物合成，导致dTTP水平耗尽，尿嘧啶掺入DNA的速率增加和基因组不稳定性。参与从头胸苷酸途径的叶酸依赖性酶包括细胞质丝氨酸羟甲基转移酶（cSHMT）、胸苷酸合成酶（TS）和二氢叶酸还原酶（DHFR）。以前，我们证明了cSHMT衍生的叶酸激活的一碳单元优先被掺入胸苷酸，我们提供的证据表明，这是通过修饰小泛素样修饰剂（SUMO）实现的，使SUMO依赖性的核定位cSHMT在S期。方法和结果：在这里，我们提供的证据表明TS和DHFR也是SUMO-1体外UBC 9催化SUMO化的底物。cSHMT、TS和DHFR的SUMO化提供了一种机制，通过该机制，胸苷酸合成途径中的所有三种酶都在细胞核中定向和区室化。
Background: Impairments in folate-mediated one-carbon metabolism are associated with pathologies and developmental anomalies, including cardiovascular disease, cancer, neurological disorders and neural tube defects. The mechanisms that detail the role of folate and one-carbon metabolism in these disorders remain to be established. Folate deficiency impairs folate-dependent thymidylate biosynthesis resulting in depleted dTTP levels, increased rates of uracil incorporation into DNA and genomic instability. Folate-dependent enzymes involved in the de novo thymidylate pathway include cytoplasmic serine hydroxymethyltransferase (cSHMT), thymidylate synthase (TS) and dihydrofolate reductase (DHFR). Previously, we demonstrated that cSHMT-derived folate activated one-carbon units are preferentially incorporated into thymidylate, and we provided evidence that this was achieved through modification with small ubiquitin-like modifier (SUMO) enabling SUMO-dependent nuclear localization of cSHMT during S-phase.Methods and results: Here, we provide evidence that TS and DHFR are also substrates for UBC9-catalyzed SUMOylation in vitro by SUMO-1.Conclusions: The SUMOylation of cSHMT, TS and DHFR provides a mechanism by which all three enzymes in the thymidylate synthesis pathway are directed and compartmentalized in the nucleus.