The mechanism of U4/U6 Di-small nuclear ribonucleoprotein formation: a modification/interference analysis

Proteins, the molecules that carry out many cellular functions, are synthesized according to information contained in DNA sequences. Converting information from DNA into a protein requires an intermediate step in which the DNA sequence is copied into a molecule called RNA. In humans there is an essential biochemical process called RNA splicing, in which non-coding portions of the sequence are removed and the remaining protein-coding portions are joined together to form a template for protein synthesis. Ninety percent of human genes are subject to splicing, so it is not surprising that errors in this process have been linked to a wide array of diseases, including retinitis pigmentosa, spinal muscular atrophy, cystic fibrosis, myotonic dystrophy, Alzheimer’s disease and cancer. Splicing is catalyzed by the spliceosome, a large and dynamic complex that consists primarily of five small nuclear ribonucleoproteins (snRNPs) designated U1, U2, U4, U5, and U6. During spliceosome assembly, the snRNPs interact with each other in a step-wise, ordered way. One of the first steps in assembly involves U4 and U6 pairing to form a particle called the U4/U6 di-snRNP. Although the di-snRNP complex is essential for spliceosome assembly and function, the mechanism by which it forms is poorly understood. Tara Wong is investigating the process by which U4 and U6 undergo essential conformational changes necessary for spliceosome assembly. She is using chemical modification/interference experiments to determine how free U4 and free U6 snRNPs interact to form the U4/U6 di-snRNP. This knowledge will be fundamental to understanding spliceosome assembly and function, and should ultimately lead to a better understanding, and treatment of splicing related diseases.