Functional roles of DExD/H-box RNA helicases in Pre-mRNA splicing

Abstract

Splicing of precursor mRNA takes place via two consecutive steps of transesterification catalyzed by a large ribonucleoprotein complex called the spliceosome. The spliceosome is assembled through ordered binding to the pre-mRNA of five small nuclear RNAs and numerous protein factors, and is disassembled after completion of the reaction to recycle all components. Throughout the splicing cycle, the spliceosome changes its structure, rearranging RNA-RNA, RNA-protein and protein-protein interactions, for positioning and repositioning of splice sites. DExD/H-box RNA helicases play important roles in mediating structural changes of the spliceosome by unwinding of RNA duplexes or disrupting RNA-protein interactions. DExD/H-box proteins are also implicated in the fidelity control of the splicing process at various steps. This review summarizes the functional roles of DExD/H-box proteins in pre-mRNA splicing according to studies conducted mostly in yeast and will discuss the concept of the complicated splicing reaction based on recent findings.

Fig. 1

Schematic representation of the spliceosome pathway and the function of the DExD/H-box proteins involved. The spliceosome pathway can be divided into four phases: spliceosome assembly, spliceosome activation, catalytic steps and spliceosome disassembly. Two DExD/H-box proteins are required for each phase of the pathway, and their functions are shown. a Sub2 is implicated in the removal of BBP/Mud2 from binding to the branch site. b Prp5 is implicated in the removal of Cus2 from U2 snRNP and converts U2 snRNA into a functional form. c Prp28 is implicated in the removal of U1C or destabilization of U1 snRNA from the 5’ splice site to promote U1/U6 switch at the 5’ splice site. d Brr2 catalyzes U4/U6 unwinding to release U4. e Prp2 is required for remodeling of the spliceosome structure by destabilization of SF3a/b. Prp2 binds to the pre-mRNA in a region downstream of the branch site and translocates in a 3’-to’5’ direction to destabilize SF3a/b. f Prp16 is required for the release of Yju2/Cwc25. g Prp22 mediates the release mature mRNA, and h Prp43 mediates spliceosome disassembly. Prp22 binds to the mature mRNA in a region downstream of the splice junction and translocates in a 3’-to’5’ direction to destabilize mRNA from the spliceosome