Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates
Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates
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DOI：
10.1021/acsinfecdis.7b00221
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发表时间：
2018-03-01
影响因子：
5.3
通讯作者：
Chelico, Linda
中科院分区：
文献类型：
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作者：
Adolph, Madison B.;Love, Robin P.;Chelico, Linda
载脂蛋白B信使核糖核酸编辑复合体(APOBEC)家族含有单链多核苷酸胞苷脱氨酶。这些酶催化RNA或单链DNA中的胞苷脱氨，形成尿嘧啶。从人类的这个11个成员的酶家族中，这里考虑了APOBEC3家族的7个成员对单链DNA的脱氨基作用。APOBEC3家族具有多种作用，如限制内源性和外源性逆转录病毒复制、逆转座子插入事件和减少DNA诱导的炎症。与其他APOBEC家族成员相似，APOBEC3酶是一把双刃剑，可以催化基因组DNA中胞嘧啶的脱氨基，由于DNA中尿嘧啶的许多突变命运，这导致了潜在的基因组不稳定。在这里，我们讨论了这些酶是如何在不同的生物环境中找到它们的单链DNA底物的，例如在人类免疫缺陷病毒(HIV)前病毒DNA合成期间，LINE-1元件的逆转录转座，以及“非靶标”的基因组DNA底物。这些酶必须能够在逆转录、复制或转录过程中有效地脱氨基。在每种情况下，特定的生化特性都会促进脱氨基作用，从而通过加工性、底物之间的快速酶循环或寡聚状态来提高酶的效率。讨论了使用生化数据来阐明生物功能和与细胞数据的一致性。提出了从生化、结构和单分子实验中连接知识的模型。
The Apolipoprotein B mRNA editing complex (APOBEC) family of enzymes contains single-stranded polynucleotide cytidine deaminases. These enzymes catalyze the deamination of cytidine in RNA or single-stranded DNA, which forms uracil. From this 11 member enzyme family in humans, the deamination of single-stranded DNA by the seven APOBEC3 family members is considered here. The APOBEC3 family has many roles, such as restricting endogenous and exogenous retrovirus replication and retrotransposon insertion events and reducing DNA-induced inflammation. Similar to other APOBEC family members, the APOBEC3 enzymes are a double-edged sword that can catalyze deamination of cytosine in genomic DNA, which results in potential genomic instability due to the many mutagenic fates of uracil in DNA. Here, we discuss how these enzymes find their single-stranded DNA substrate in different biological contexts such as during human immunodeficiency virus (HIV) proviral DNA synthesis, retrotransposition of the LINE-1 element, and the "off-target" genomic DNA substrate. The enzymes must be able to efficiently deaminate transiently available single-stranded DNA during reverse transcription, replication, or transcription. Specific biochemical characteristics promote deamination in each situation to increase enzyme efficiency through processivity, rapid enzyme cycling between substrates, or oligomerization state. The use of biochemical data to clarify biological functions and alignment with cellular data is discussed. Models to bridge knowledge from biochemical, structural, and single molecule experiments are presented.