Background: DNA and RNA of most cellular life forms and many viruses contain an expansive repertoire of modified bases. The modified bases play diverse biological roles that include both regulation of transcription and translation, and protection against restriction endonucleases and antibiotics. Modified bases are often recognized by dedicated protein domains. However, the elaborate networks of interactions and processes mediated by modified bases are far from being completely understood. Results: We present a comprehensive census and classification of EVE domains that belong to the PUA/ASCH domain superfamily and bind various modified bases in DNA and RNA. Prokaryotes encode two classes of EVE domain proteins, slow-evolving and fast-evolving. The slow-evolving EVE domains in alpha-proteobacteria are embedded in a conserved operonic context that implies involvement in coupling between translation and respiration, in particular, cytochrome c biogenesis, potentially, via binding 5-methylcytosine in tRNAs. In beta and gamma-proteobacteria, the conserved associations implicate the EVE domains in the coordination of cell division, biofilm formation, and global transcriptional regulation by non-coding 6S small RNAs, which are potentially modified and bound by the EVE domains. Down-regulation of the EVE-encoding operons might cause dormancy or programmed cell death (PCD). In eukaryotes, the EVE-domain-containing THYN1-like proteins appear to inhibit PCD and regulate the cell cycle, likely, via binding 5-methylcytosine and its derivatives in DNA and/or RNA. Thus, the link between PCD and cytochrome c that appears to be universal in eukaryotes might have been inherited from the α-proteobacterial, proto-mitochondrial endosymbiont and, unexpectedly, could involve modified base recognition by EVE domains. In numerous prokaryotic genomes, fast-evolving EVE domains are embedded in defense contexts, including toxin-antitoxin modules and Type IV restriction systems, all of which can also induce PCD. These EVE domains likely recognize modified bases in invading DNA molecules and target them for restriction. We additionally identified EVE-like prokaryotic Development and Cell Death (DCD) domains that are also implicated in defense functions including PCD. This function was inherited by eukaryotes but, in animals, the DCD proteins apparently were displaced by the extended Tudor family, whose partnership with Piwi-related Argonautes became the centerpiece of the piRNA system. Conclusions: Recognition of modified bases in DNA and RNA by EVE-like domains appears to be an important, but until now, under-appreciated, common denominator in a variety of processes including PCD, cell cycle control, antivirus immunity, stress response and germline development in animals.

中文翻译：

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修改的碱基结合的EVE和DCD域涉及程序性细胞死亡和piRNA途径的起源。

背景：大多数细胞生命形式的DNA和RNA以及许多病毒都含有大量的修饰碱基。修饰的碱基起多种生物学作用，包括调节转录和翻译，以及针对限制性核酸内切酶和抗生素的保护。修饰的碱基通常被专用的蛋白质结构域识别。然而，由修饰的碱基介导的相互作用和过程的复杂网络远未完全被理解。结果：我们对属于PUA / ASCH域超家族并结合DNA和RNA中各种修饰碱基的EVE域进行了全面的人口普查和分类。原核生物编码两类EVE结构域蛋白：缓慢进化和快速进化。α-变形杆菌中缓慢发展的EVE结构域嵌入保守的操纵子环境中，这暗示着可能通过结合tRNA中的5-甲基胞嘧啶参与翻译和呼吸作用之间的耦合，特别是参与细胞色素C的生物发生。在β和γ-变形杆菌中，保守的关联通过非编码6S小RNA暗示EVE结构域参与细胞分裂，生物膜形成和全局转录调控，这些可能被EVE结构域修饰和结合。EVE编码操纵子的下调可能会导致休眠或程序性细胞死亡（PCD）。在真核生物中，含有EVE域的THYN1样蛋白似乎可以抑制PCD并调节细胞周期，这可能是通过结合DNA和/或RNA中的5-甲基胞嘧啶及其衍生物来实现的。从而，在真核生物中普遍存在的PCD和细胞色素c之间的联系可能是从α-变形细菌，线粒体原内共生体继承而来的，而且出乎意料的是，它可能涉及EVE结构域对碱基识别的修饰。在许多原核生物基因组中，快速进化的EVE域嵌入防御环境中，包括毒素-抗毒素模块和IV型限制系统，所有这些都可以诱导PCD。这些EVE域可能识别入侵的DNA分子中的修饰碱基，并以其为限制性靶标。我们还确定了类似EVE的原核发育和细胞死亡（DCD）域，这些域也与包括PCD在内的防御功能有关。这种功能是由真核生物继承的，但是在动物中，DCD蛋白显然被延伸的Tudor家族所取代，他与Piwi相关的Argonautes的合作关系成为piRNA系统的核心。结论：通过EVE样结构域识别DNA和RNA中修饰的碱基似乎很重要，但直到现在，在PCD，细胞周期控制，抗病毒免疫，应激反应和种系等多种过程中，人们的价值均未得到充分认识。动物的发展。