Nucleic acid oxidation in DNA damage repair and epigenetics.
Nucleic acid oxidation in DNA damage repair and epigenetics.
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DOI：
10.1021/cr400432d
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发表时间：
2014-04-23
期刊：
影响因子：
62.1
通讯作者：
He, Chuan
中科院分区：
文献类型：
--
作者：
Zheng, Guanqun;Fu, Ye;He, Chuan
甲基化是核酸和蛋白质中广泛发生的化学修饰。细胞外或细胞内的甲基化剂可攻击DNA中的脆弱位点，这可导致细胞毒性和/或致癌性DNA损伤。甲基化在生物学中也起着关键的信号作用。使用S-腺苷甲硫氨酸（SAM）作为甲基基团的最常见的亲电来源，各种甲基转移酶修饰DNA、RNA和蛋白质以产生影响基因表达调控的不同生物甲基化。1，2尽管甲基化的重要性得到了广泛的认可，但去甲基化过程，特别是氧化去甲基化，最近受到了广泛的关注，这在很大程度上是由于其细胞调节功能。去甲基化与甲基化一起不断地塑造生物分子的甲基化组。这篇评论的重点是氧化去甲基化介导的一个家庭的单核含铁（II）酶。这个酶家族的成员最初是作为DNA修复蛋白被发现的，它可以氧化逆转DNA甲基化损伤。近年来的后续研究揭示了这些去甲基化酶通过DNA、RNA和组蛋白上的表观遗传甲基化的去甲基化在控制基因表达中的更广泛和重要的作用。甲基化剂引起的DNA甲基化损伤可发生在碱基或主链的不同位置。位置取决于化学反应类型（SN 1或SN 2亲核取代）以及位置的敏感性。一般来说，SN 1型甲基化试剂（例如，N-甲基-N′-亚硝基脲，MNU）甲基化核酸中的氮和氧原子，而SN 2型试剂（例如，甲磺酸甲酯，MMS）倾向于攻击暴露碱基的亲核N位（图1A）。3− 5由此产生的损伤表现出不同水平的细胞毒性和致突变影响，并且可以通过亲核取代或氧化去甲基化被酶迅速逆转（图1B）。3，6本综述仅讨论氧化去甲基化修复途径。N1-甲基腺嘌呤（m1A）和N3-甲基胞嘧啶（m3 C）是在SN 2型甲基化剂存在下在单链DNA（ssDNA）中形成的主要损伤。3、4、6这两个位置的甲基化在DNA复制期间损害沃森-克里克碱基配对，导致细胞毒性。7通过10年前发现的前所未有的氧化去甲基化机制，FeII/α-酮戊二酸-（α-KG-）依赖性AlkB家族双加氧酶可以修复这些甲基化DNA损伤。8，9从那时起，执行类似修复功能的人类同源物已被鉴定。对属于同一大家族的其他同源物或蛋白质的研究已经揭示了一系列去甲基化功能，这些功能可以逆转高等植物中组蛋白、RNA和DNA上的表观遗传甲基化。
Methylation is a widely occurring chemical modification in nucleic acids and proteins. Methylating agents, either extracellular or intracellular, can attack vulnerable sites in DNA, which can lead to cytotoxic and/or cancerogenic DNA damages. Methylation also plays critical signaling roles in biology. Using S-adenosylmethionine (SAM) as the most common electrophilic source of methyl groups, various methyltransferases modify DNA, RNA, and proteins to generate different biological methylations that impact gene expression regulation. 1, 2 Whereas the significance of methylation is widely appreciated, the demethylation process, oxidative demethylation in particular, has received much recent attention due in large part to its cellular regulatory functions. Demethylation, together with methylation, continuously sculpts the methylomes of biomolecules. This review focuses on oxidative demethylation as mediated by a family of mononuclear iron (II)-containing enzymes. The members of this family of enzymes were first discovered as DNA-repair proteins that oxidatively reverse DNA methylation damage. Subsequent research in recent years has revealed much broader and significant roles of these demethylases in controlling gene expression through the demethylation of epigenetic methylations on DNA, RNA, and histones. DNA methylation damage caused by methylating agents can occur on different positions of bases or backbones. The location depends on the chemical reaction type (SN1 or SN2 nucleophilic substitution), as well as the susceptibility of the position. In general, the SN1 type of methylating agent (eg, N-methyl-N′-nitrosourea, MNU) methylates both nitrogen and oxygen atoms in nucleic acids, whereas the SN2-type agents (eg, methylmethane sulfonate, MMS) tend to attack the nucleophilic N-position of exposed bases (Figure 1A). 3− 5 The resulting lesions exhibit different levels of cellular toxicity and mutagenic influence and can be promptly reversed by enzymes through either nucleophilic substitutions or oxidative demethylations (Figure 1B). 3, 6 This review discusses the oxidative demethylation repair pathway only. N1-Methyladenine (m1A) and N3-methylcytosine (m3C) are major lesions formed in single-stranded DNA (ssDNA) in the presence of SN2-type methylating agents. 3, 4, 6 Methylations in these two positions compromise Watson− Crick base pairing during DNA replication, resulting in cytotoxcity. 7 Through an unprecedented oxidative demethylation mechanism revealed over 10 years ago, the FeII/α-ketoglutarate-(α-KG-) dependent AlkB family dioxygenases can repair these methylating DNA lesions. 8, 9 Since then, human homologues that perform similar repair functions have been identified. Studies of other homologues or proteins belonging to the same general family have uncovered a range of demethylation functions that reverse epigenetic methylations on histones, RNA, and DNA in higher
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影响因子：
16
作者：
Begley, Ulrike;Dyavaiah, Madhu;Begley, Thomas J.
通讯作者：
Begley, Thomas J.
DOI：
10.1016/0027-5107(90)90173-2
发表时间：
1990-07-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
BERANEK, DT
通讯作者：
BERANEK, DT
影响因子：
3.9
作者：
Bleijlevens, Boris;Shivarattan, Tara;Matthews, Steve J.
通讯作者：
Matthews, Steve J.
影响因子：
14.9
作者：
Bodi Z;Button JD;Grierson D;Fray RG
通讯作者：
Fray RG
影响因子：
4.4
作者：
Bratlie MS;Drabløs F
通讯作者：
Drabløs F