Modulation of DNA methyltransferase profile by methyl donor starvation followed by gamma irradiation
Modulation of DNA methyltransferase profile by methyl donor starvation followed by gamma irradiation
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DOI：
10.1007/s11010-006-9258-8
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发表时间：
2007-01-01
影响因子：
4.3
通讯作者：
Mishra, Kaushala P.
中科院分区：
文献类型：
--
作者：
Batra, Vipen;Mishra, Kaushala P.
DNA甲基化是一种重要的表观遗传转录调控机制，在维持细胞功能中起着重要作用。一碳转移剂/甲基供体即叶酸、胆碱和甲硫氨酸在DNA甲基化中的作用已经成为广泛研究的主题。DNA的甲基化模式在胚胎发生期间通过DNA甲基转移酶3（dnmt 3）建立，随后通过酶DNA甲基转移酶1（dnmt 1）的维持甲基化活性来维持。已知电离辐射会广泛破坏DNA。已知足够的甲基供体的膳食可用性有助于一碳转移介导的受损DNA的修复，其中叶酸参与核苷酸碱基合成。在本研究中，观察到甲基供体饥饿，然后γ-照射的dnmt 1和dnmt 3的活动的修改。测定基于H-3-甲基从S-腺苷-L-甲硫氨酸催化转移至DNA底物。实验表明，剂量和甲基供体饥饿依赖的衰减dnmt 1活性。dnmt 1活性的衰减是最显着的饮食剥夺了所有的三个甲基供体。当去除膳食甲基供应的三种可能来源之一或全部时，细胞核或细胞质dnmt 3活性没有观察到显着变化。观察到电离辐射和甲基供体缺乏对抑制dnmt 1活性起协同作用。目前的研究结果表明，叶酸，蛋氨酸和胆碱缺乏症之间的相互作用，以加强电离辐射应激的症状的可能性。这些酶的修饰可能有助于改变DNA甲基化后，长期喂养甲基供体自由饮食，然后γ射线照射。这些结果表明，甲基供体的膳食可用性和γ辐射应激可能会显着改变dnmt 1谱。
DNA methylation is an important epigenetic mechanism of transcriptional control, which plays an essential role in maintaining cellular function. Role of one-carbon transfer agents/methyl donors namely folate, choline and methionine in DNA methylation has been the subject of extensive investigation. The methylation pattern of DNA is established during embryogenesis by DNA methyltransferase 3 (dnmt3) and is subsequently maintained by maintenance methylation activity of the enzyme DNA methyltransferase 1 (dnmt1). Ionizing radiation is known to extensively damage the DNA. Sufficient dietary availability of methyl donors is known to contribute towards one-carbon transfer mediated repair of damaged DNA where folate is involved in nucleotide base synthesis. In the present study, modification in activities of dnmt1 and dnmt3 by methyl donor starvation followed by gamma-irradiation was observed. Assays were based on the catalytic transfer of H-3-methyl groups from S-adenosyl-L-methionine to a DNA substrate. Experiments showed a dose and methyl donors starvation dependent attenuation in dnmt1 activity. Attenuation of dnmt1 activity was most significant for diet deprived of all the three-methyl donors. No significant change in nuclear or cytoplasmic dnmt3 activity was observed when either or all the three possible source of dietary methyl group supply were removed. Ionizing radiation and methyl donor deficiency were observed to act synergistically towards inhibiting dnmt1 activity. Present results suggested possibility of interaction among folate, methionine and choline deficiency to potentiate symptoms of ionizing radiation stress. These enzymatic modifications might contribute to altered DNA methylation after chronic feeding of methyl donor free diets followed by gamma irradiation. These results suggested that dietary availability of methyl donors and gamma-radiation stress might significantly alter the dnmt1 profile.