Abstract

BackgroundDNA and RNA of all 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.ResultsWe 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. We employ the “guilt by association” approach to make functional inferences from comparative analysis of bacterial and archaeal genomes, based on the distribution and associations of EVE domains in (predicted) operons and functional networks of genes. Prokaryotes encode two classes of EVE domain proteins, slow-evolving and fast-evolving ones. Slow-evolving EVE domains in α-proteobacteria are embedded in conserved operons, potentially involved in coupling between translation and respiration, cytochrome c biogenesis in particular, via binding 5-methylcytosine in tRNAs. In β- and γ-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. In eukaryotes, the EVE domain-containing THYN1-like proteins have been reported to inhibit PCD and regulate the cell cycle, potentially, via binding 5-methylcytosine and its derivatives in DNA and/or RNA. We hypothesize that the link between PCD and cytochrome c was inherited from the α-proteobacterial and proto-mitochondrial endosymbiont and, unexpectedly, could involve modified base recognition by EVE domains. Fast-evolving EVE domains are typically embedded in defense contexts, including toxin-antitoxin modules and type IV restriction systems, suggesting roles in the recognition of modified bases in invading DNA molecules and targeting 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 proteins, whose partnership with Piwi-related Argonautes became the centerpiece of the Piwi-interacting RNA (piRNA) system.ConclusionsRecognition 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.

Highlights

  • DNA and RNA of all cellular life forms and many viruses contain an expansive repertoire of modified bases

  • A census of EVE proteins Our search for EVE proteins using PSI-BLAST and HHpred seeded with profiles derived from multiple alignments of the amino acid sequences of known EVE domains showed that the EVE domain is most prevalent among Proteobacteria, which harbor the majority of all prokaryotic EVE proteins detected (Additional file 1: Fig. S1) and a plurality of all EVE proteins

  • The overarching theme is involvement in immunity, self- vs non-self-discrimination, and stress response/programmed cell death (PCD), whether that be through targeting of modified DNA for restriction in diverse prokaryotes, regulation of the proliferation-PCD-dormancy balance in Proteobacteria and eukaryotes, or export and translation of spliced and modified mRNAs in choanoflagellates

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Summary

Introduction

DNA and RNA of all cellular life forms and many viruses contain an expansive repertoire of modified bases. DNA and different types of RNA of all organisms and diverse viruses contain a variety of modified bases These derivatives of the canonical purines and pyrimidines perform a broad range of biological functions including regulation of transcription and translation as well as selfversus non-self-discrimination that is required for protection against biological defense and offense systems, such as restriction endonucleases and antibiotics [1,2,3,4,5,6]. Sequence and structure analyses have shown that the EVE domain is a member of the PUA (pseudouridine synthase and archaeosine transglycosylase)/ASCH (ASC-1 homology) superfamily, a widely disseminated and apparently ancient assemblage of nucleic acid-binding domains [8,9,10,11,12,13]. Some ASCH domains have been predicted to bind modified bases [15]

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