Opening new doors for understanding eukaryotic RNA splicing

Abstract

Since the central dogma of molecular biology was proposed by Francis Crick in 1956, many fundamental discoveries have been made to strengthen or expand the theory for gene expression. Nowadays, we know that genetic information flow in a cell is a far more complicated process than the original succinct but explicit version. We now know that besides DNA duplication, DNA to RNA transcription, RNA to protein translation, there are also RNA to DNA transcription (reverse transcription), RNA to RNA replication, and RNA splicing and processing between the transcription and translation steps. Modifications and other processes to regulate and fine-tune gene expression have also been discovered in most recent years. All of these events are executed by multiple supramolecular machineries such as DNA and RNA polymerases, ribosomes, and spliceosomes. These machineries are normally multi-functional complexes composed of dozens of protein and RNA molecules and their activities are regulated by many other co-factor proteins or RNA molecules.In the past few decades, structural biology, as a tool to decipher the precise atomic coordinates within a molecule, has played essential roles in elucidating most of the critical steps in gene expression. The atomic models of DNA polymerases revealed how DNA is duplicated; the atomic model of RNA polymerase complex explained in great detail of how RNA is transcribed from its DNA gene; the structures of ribosome in its various states described vividly how proteins are translated from messenger RNAs. Not only were the structures of the major molecular machines involved in the aforementioned processes solved, but also their different working states and regulatory co-factors have been revealed in great structural details. These structures brought major leaps for our understanding of central dogma. In contrast, a major step of the gene expression, RNA splicing, is still largely a jigsaw puzzle in fog, due to the lack of structural information of the major machinery, the spliceosome. More than 30 years after its first component was discovered, the highest resolution of spliceosome complex was only solved at about 20 Å using electron microscopy, far away for us to understand the detailed mechanism of how RNA splicing is performed. This embarrassing situation now gets to a turning point to catch up soon with other central dogma steps. The most recently solved spliceosome complex structure at near atomic resolution by professor Yigong Shi and his colleagues in Tsinghua University wipes off the fog and opens new doors for understanding RNA splicing in a new foreground [1,2].Almost all RNA transcripts in eukaryotic cells need additional processing steps before their maturation. The most critical processing step for messenger RNAs (mRNA) is the splicing, which removes the non-coding region (intron) and ligates the coding regions (exon) from a newly transcribed RNA to generate a mature RNA for translation. In splicing, the two ends of an intron are brought to spatial proximity for two successive trans-es...