AID, APOBEC3A and APOBEC3B efficiently deaminate deoxycytidines neighboring DNA damage induced by oxidation or alkylation
AID, APOBEC3A and APOBEC3B efficiently deaminate deoxycytidines neighboring DNA damage induced by oxidation or alkylation
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DOI：
10.1016/j.bbagen.2019.129415
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发表时间：
2019-11-01
影响因子：
3
通讯作者：
Larijani, Mani
中科院分区：
文献类型：
--
作者：
Diamond, Cody P.;Im, Junbum;Larijani, Mani
背景：AID/APOBEC 3（A3）酶引发参与免疫和癌症的基因组突变。虽然它们可以将任何脱氧胞苷（dC）脱氨基为脱氧尿苷（dU），但每个家族成员都具有由靶dC周围的核苷酸决定的特征偏好。分别针对AID和A3 A/A3 B建立该WRC（W = A/T，R = A/G）和YC（Y = T/C）热点偏好。碱基烷基化和氧化是环境或化疗诱导的两种最常见的DNA损伤类型。在这里，我们研究了AID，A3 A和A3 B对dCs相邻的这种损坏bases.Methods的活动：基板被设计成包含目标dCs在正常的WRC/YC热点，或在氧化/烷基化的DNA基序。AID，A3 A和A3 B进行纯化和脱氨基动力学的每一个进行了比较，含有受损与正常motifs.Results：所有三种酶有效地脱氨基dC时，常见的受损碱基存在于-2或-1的位置。引人注目的是，一些受损的基序支持AID，A3 A和A3 B的催化效率比WRC/YC基序，这是他们最喜欢的正常序列相当或更高。基于AID，A3 A和A3 B与DNA的解析相互作用，我们模拟了与烷基化或氧化碱基的相互作用。确证的酶测定数据，识别正常的碱基的表面区域预测也相互作用鲁棒与氧化和烷基化bases.Conclusions：AID，A3 A和A3 B可以有效地识别和deaminate dC其相邻的核苷酸damaged.General意义：除了AID/A3 s启动DNA损伤，一些形式的预先存在的受损DNA可以构成有利的目标AID/A3 s如果遇到。
Background: AID/APOBEC3 (A3) enzymes instigate genomic mutations that are involved in immunity and cancer. Although they can deaminate any deoxycytidine (dC) to deoxyuridine (dU), each family member has a signature preference determined by nucleotides surrounding the target dC. This WRC (W = A/T, R = A/G) and YC (Y = T/C) hotspot preference is established for AID and A3A/A3B, respectively. Base alkylation and oxidation are two of the most common types of DNA damage induced environmentally or by chemotherapy. Here we examined the activity of AID, A3A and A3B on dCs neighboring such damaged bases.Methods: Substrates were designed to contain target dCs either in normal WRC/YC hotspots, or in oxidized/alkylated DNA motifs. AID, A3A and A3B were purified and deamination kinetics of each were compared between substrates containing damaged vs. normal motifs.Results: All three enzymes efficiently deaminated dC when common damaged bases were present in the -2 or -1 positions. Strikingly, some damaged motifs supported comparable or higher catalytic efficiencies by AID, A3A and A3B than the WRC/YC motifs which are their most favored normal sequences. Based on the resolved interactions of AID, A3A and A3B with DNA, we modeled interactions with alkylated or oxidized bases. Corroborating the enzyme assay data, the surface regions that recognize normal bases are predicted to also interact robustly with oxidized and alkylated bases.Conclusions: AID, A3A and A3B can efficiently recognize and deaminate dC whose neighbouring nucleotides are damaged.General significance: Beyond AID/A3s initiating DNA damage, some forms of pre-existing damaged DNA can constitute favored targets of AID/A3s if encountered.