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Cartoon of the splicing process. The RUVBL1-RUVBL2-ZNHIT2 complex is one of several factors required for the assembly and maturation of the spliceosome. Right panel shows one view of the cryo-EM map of the RUVBL1-RUVBL2-ZNHIT2 complex determined in this study./CNIO
DNA contains the instructions for life, which need to be read in order to build proteins, which are the agents ultimately responsible for the myriad of processes necessary to construct and maintain a living organism, for example by activating muscle movement or by defending it from the viruses. Splicing is a cellular mechanism that facilitates the reading and multiplies the number of potential protein sequences in a cell by allowing the synthesis of several different proteins from a single gene. Researchers from the Spanish National Cancer Research Centre (CNIO) led by Óscar Llorca, director of the Structural Biology Programme and head of the Macromolecular Complexes in DNA Damage Response Group, have shed light on this complex cellular process and, in particular, on the role of RUVBL1 and RUVBL2 proteins. The study is published in the journal Nucleic Acids Research.
Alternative Splicing is an extraordinarily complex process that requires the coordinated action of multiple proteins, each specialised in very specific functions. These proteins are assembled and matured, forming a kind of consortium of proteins that perform these gene reading functions. The assembly process is tightly controlled, and any failure can result in genetic diseases, including some types of cancer.
In this study, the researchers have explored some of the factors that enable the assembly and maturation of the spliceosome, a multi-megadalton complex responsible for cell splicing and alternative splicing, specifically in the proteins RUVBL1 and RUVBL2. The study of the atomic structure of these proteins by means of Cryo-Electron microscopy (cryo-EM), among other techniques, has revealed their functioning: RUVBL1 and RUVBL2 operate as scaffolding that interacts and connects components of the splicing machinery with various factors necessary for maturation, which, in turn, control the activity of the RUVBL1-RUVBL2 complex.
These results help us to understand some of the mechanisms responsible for the maturation of the splicing machinery. Several types of cancer present failures in the splicing processes, which is an advantage for tumour cells since these failures improve their rate of survival. “If we understand in detail the assembly and maturation mechanism of the spliceosome and the factors that control it, we will also be able to understand essential processes for life and their role in diseases such as cancer”, stated the researchers.
This study was funded by the Ministry of Science and Innovation, the Carlos III Health Institute, Madrid’s Regional Government, the European Regional Development Fund, and the Amigos del CNIO philanthropy programme.
Reference article: CryoEM of RUVBL1–RUVBL2–ZNHIT2, a complex that interacts with pre-mRNA-processing-splicing factor 8. Marina Serna et al. (Nucleic Acids Research., 2021). DOI: 10.1093/nar/gkab1267