Coding From Binding? Molecular Interactions at the Heart of Translation.

The mechanism and the evolution of DNA replication and transcription, the key elements of the central dogma of biology, are fundamentally well explained by the physicochemical complementarity between strands of nucleic acids. However, the determinants that have shaped the third part of the dogma-the process of biological translation and the universal genetic code-remain unclear. We review and seek parallels between different proposals that view the evolution of translation through the prism of weak, noncovalent interactions between biological macromolecules. In particular, we focus on a recent proposal that there exists a hitherto unrecognized complementarity at the heart of biology, that between messenger RNA coding regions and the proteins that they encode, especially if the two are unstructured. Reflecting the idea that the genetic code evolved from intrinsic binding propensities between nucleotides and amino acids, this proposal promises to forge a link between the distant past and the present of biological systems.

Widespread autogenous mRNA-protein interactions detected by CLIP-seq.

Autogenous interactions between mRNAs and the proteins they encode are implicated in cellular feedback-loop regulation, but their extent and mechanistic foundation are unclear. It was recently hypothesized that such interactions may be common, reflecting the role of intrinsic nucleobase-amino acid affinities in shaping the genetic code's structure. Here we analyze a comprehensive set of CLIP-seq experiments involving multiple protocols and report on widespread autogenous interactions across different organisms. Specifically, 230 of 341 (67%) studied RNA-binding proteins (RBPs) interact with their own mRNAs, with a heavy enrichment among high-confidence hits and a preference for coding sequence binding. We account for different confounding variables, including physical (overexpression and proximity during translation), methodological (difference in CLIP protocols, peak callers and cell types) and statistical (treatment of null backgrounds). In particular, we demonstrate a high statistical significance of autogenous interactions by sampling null distributions of fixed-margin interaction matrices. Furthermore, we study the dependence of autogenous binding on the presence of RNA-binding motifs and structured domains in RBPs. Finally, we show that intrinsic nucleobase-amino acid affinities favor co-aligned binding between mRNA coding regions and the proteins they encode. Our results suggest a central role for autogenous interactions in RBP regulation and support the possibility of a fundamental connection between coding and binding.

POSTAR3: an updated platform for exploring post-transcriptional regulation coordinated by RNA-binding proteins.

RNA-binding proteins (RBPs) play key roles in post-transcriptional regulation. Accurate identification of RBP binding sites in multiple cell lines and tissue types from diverse species is a fundamental endeavor towards understanding the regulatory mechanisms of RBPs under both physiological and pathological conditions. Our POSTAR annotation processes make use of publicly available large-scale CLIP-seq datasets and external functional genomic annotations to generate a comprehensive map of RBP binding sites and their association with other regulatory events as well as functional variants. Here, we present POSTAR3, an updated database with improvements in data collection, annotation infrastructure, and analysis that support the annotation of post-transcriptional regulation in multiple species including: we made a comprehensive update on the CLIP-seq and Ribo-seq datasets which cover more biological conditions, technologies, and species; we added RNA secondary structure profiling for RBP binding sites; we provided miRNA-mediated degradation events validated by degradome-seq; we included RBP binding sites at circRNA junction regions; we expanded the annotation of RBP binding sites, particularly using updated genomic variants and mutations associated with diseases. POSTAR3 is freely available at http://postar.ncrnalab.org.