Molecular basis for the reversible ADP-ribosylation of guanosine bases
Molecular basis for the reversible ADP-ribosylation of guanosine bases
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鸟苷碱基可逆 ADP-核糖基化的分子基础
DOI：
10.1016/j.molcel.2023.06.013
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发表时间：
2023
期刊：
影响因子：
16
通讯作者：
Schuller M
中科院分区：
文献类型：
--
作者：
Schuller M
ADP-核糖基化对核酸的修饰由多种 ADP-核糖基转移酶（包括 DarT 酶）催化。后者是细菌毒素-抗毒素 (TA) 系统 DarTG 的一部分，该系统被证明可以控制 DNA 复制和细菌生长，并提供针对噬菌体的保护。已鉴定出两个亚家族：DarTG1 和 DarTG2，它们通过相关的抗毒素进行区分。虽然 DarTG2 使用大结构域作为抗毒素催化胸苷碱基的可逆 ADP-核糖基化，但 DarTG1 的 DNA ADP-核糖基化活性及其抗毒素（NADAR 结构域）的生化功能尚不清楚。使用结构和生化方法，我们证明 DarT1-NADAR 是鸟苷碱基可逆 ADP-核糖基化的 TA 系统。 DarT1 进化出了将 ADP-核糖与鸟嘌呤氨基连接的能力，鸟嘌呤氨基可被 NADAR 特异性水解。我们发现，鸟嘌呤脱 ADP-核糖基化在真核生物和非 DarT 相关 NADAR 成员中也是保守的，表明可逆鸟嘌呤修饰在 DarTG 系统之外广泛分布。
Modification of nucleic acids by ADP-ribosylation is catalyzed by various ADP-ribosyltransferases, including the DarT enzyme. The latter is part of the bacterial toxin-antitoxin (TA) system DarTG, which was shown to provide control of DNA replication and bacterial growth as well as protection against bacteriophages. Two subfamilies have been identified, DarTG1 and DarTG2, which are distinguished by their associated antitoxins. While DarTG2 catalyzes reversible ADP-ribosylation of thymidine bases employing a macrodomain as antitoxin, the DNA ADP-ribosylation activity of DarTG1 and the biochemical function of its antitoxin, a NADAR domain, are as yet unknown. Using structural and biochemical approaches, we show that DarT1-NADAR is a TA system for reversible ADP-ribosylation of guanosine bases. DarT1 evolved the ability to link ADP-ribose to the guanine amino group, which is specifically hydrolyzed by NADAR. We show that guanine de-ADP-ribosylation is also conserved among eukaryotic and non-DarT-associated NADAR members, indicating a wide distribution of reversible guanine modifications beyond DarTG systems.