DNA硫修饰基础理论突破驱动合成生物学系统创新

DNA modification by sulfur: mechanistic insights drives synthetic biotechnologies forward

摘要:

DNA作为生命体的遗传物质，除包含4种碱基之外，还具有多种多样的修饰类型。自100年前DNA甲基化首次被发现以来，科研人员已在天然DNA中鉴定出17种以上的化学修饰，包括5-甲基胞嘧啶(5-methylcytosine, 5mC)、N6-甲基腺苷(N6-methyladenosine, 6mA)、N4-甲基胞嘧啶(N4-methylcytosine, 4mC)、5-羟甲基胞嘧啶(5-hydroxymethylcytosine, 5hmC)等。这些修饰在维持碱基配对特性的同时，可通过改变DNA-蛋白质相互作用参与调控多种生理过程并影响疾病发生。值得注意的是，早期发现的修饰均局限于碱基层面，而DNA硫修饰是首次在天然DNA骨架中发现了新元素，也是首次在DNA磷酸骨架上发现的天然修饰。在硫修饰DNA中，DNA磷酸骨架上的非桥接氧原子被硫原子取代，形成磷硫酰化修饰。近年来，关于DNA硫修饰的分布规律、基因组序列偏好性及其生物学功能的研究取得了显著进展。本研究系统阐述了DNA硫修饰相关的细菌防御系统和硫修饰特异性识别机制，并介绍了DNA硫修饰在合成生物学领域的前沿应用，特别是在基因编辑、核酸检测、抗噬菌体工业底盘菌方面的独特价值，为医学诊疗和工业生产提供了有力的技术支撑。

Abstract:

As the genetic material of living organisms, DNA contains diverse chemical modifications beyond the four bases. Since the first discovery of DNA methylation a century ago, over 17 natural DNA modifications have been identified, including 5-methylcytosine (5mC), N6-methyladenosine (6mA), N4-methylcytosine (4mC), and 5-hydroxymethylcytosine (5hmC). These modifications typically do not affect base pairing but may modulate DNA-protein interactions, thereby playing critical roles in physiological processes and disease occurrence. Early studies predominantly focused on base modifications, while the discovery of DNA sulfur modification marked a breakthrough—the first natural modification involving a new element (sulfur) replacing the non-bridging oxygen species in the DNA phosphodiester bond backbone, forming a phosphorothioate (PT) linkage. Recent studies have elucidated the genomic distribution, sequence context, and biological functions of PT modifications. This review highlights the bacterial defense systems associated with PT modifications, their molecular recognition mechanisms, and emerging applications as enabling technologies in gene editing, nucleic acid detection, and bacteriophage-resistant industrial strain development, providing insights for synthetic biology.