What structural features determine repair enzyme specificity and mechanism in chemically modified DNA?
What structural features determine repair enzyme specificity and mechanism in chemically modified DNA?
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哪些结构特征决定了化学修饰 DNA 中修复酶的特异性和机制？
DOI：
10.1021/tx970011e
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Hang,B
中科院分区：
文献类型：
--
作者：
Singer,B;Hang,B
防止DNA碱基化学修饰所致突变的基本机制之一被称为“修复”。在体内和体外，当一个修饰的碱基被“修复酶”识别时，焦点通常集中在DNA加合物被切断或修饰被逆转的机制上。在现实中，修复必须至少是一个两步的过程，在这个过程中，切除之后是复制。一个例外是通过O-烷基甲基转移酶，它不需要切除就能恢复正常的碱基。对这些过程的详细了解在很大程度上仍然未知，特别是在哺乳动物细胞中。然而，有许多优秀的评论专门涉及将DNA恢复到其未受损状态的完整过程(1-18)。修复的第一步是酶对损伤的识别，这一观点将限于讨论是什么决定了修饰的碱基或AP(无嘌呤/无嘧啶)1位点是如何被切除或逆转的，以及这些修复酶的特异性。至少有三种原核生物和真核生物修复的基本机制是众所周知的。它们是(1)碱基切除修复，(2)核苷酸切除修复，和(3)仅通过去除O-甲基(或烷基)转移酶所示的修饰基团来直接逆转(图1)。也有报道称，其中两条通路可以在同一病变上进行手术。每种类型的酶都有完整的序列数据，以及一些晶体结构。例如尿嘧啶-DNA糖基酶(19-22)、烷基或3-甲基腺嘌呤(M3A)-DNA糖基酶(23-29)、核酸内切酶III或胸腺嘧啶二醇-DNA糖基酶(30-32)、AP内切酶(33-37)和O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)(38-41)。修复数据的优势来自使用原核酶的研究，但我们将尽可能讨论真核酶，最好是人类来源的酶。我们感到遗憾的是，这一视角的焦点不允许充分承认许多科学家的原始发现，即大量加合物是通过未确定的酶活性从细胞或哺乳动物中移除的。例如，在此之前
One of the basic mechanisms for prevention of mutagenesis resulting from chemical modification of DNA bases is termed “repair”. In vivo and in vitro, when a modified base is recognized by “repair enzymes”, the focus is generally on the mechanism by which an adduct is cut out of DNA or the modification is reversed. In reality, repair has to be at least a two-step process in which excision is followed by replication. One exception is through O-alkylmethyltransferase which restores the normal base without excision. The detailed understanding of these processes is still largely unknown, particularly in mammalian cells. There are, however, many excellent reviews specifically related to the complete process of restoring DNA to its undamaged state (1-18). The initial step in repair is enzyme recognition of damage, and this Perspective will be restricted to a discussion of the knowledge, and lack thereof, of what determines how a modified base or AP (apurinic/apyrimidinic) 1 site is excised or reversed, as well as the specificity of these repair enzymes. At least three basic mechanisms for repair by both prokaryotes and eukaryotes are well known. These are (1) base excision repair,(2) nucleotide excision repair, and (3) direct reversal by removal of only a modified group as illustrated by O-methyl (or alkyl) transferase (Figure 1). It has also been reported that two of these pathways can be operative on the same lesion. Complete sequence data are available for each of the types of enzymes, as well as some crystal structures. Examples are uracil-DNA glycosylases (19-22), AlkA or 3-methyladenine (m3A)-DNA glycosylases (23-29), endonuclease III or thymine glycol-DNA glycosylases (30-32), AP endonucleases (33-37), and O6-methylguanine-DNA methyltransferases (MGMTs)(38-41). The preponderance of repair data comes from research using prokaryotic enzymes, but we will discuss, whenever possible, eukaryotic enzymes, preferably of human origin. We regret that the focus of this Perspective does not permit adequate acknowledgment of the many scientists who made the original findings that a large number of adducts were removed from cells or mammals by uncharacterized enzymatic activity. For example, prior to