Song, Eun Joo Werner, Shannon L. Neubauer, Jakob Stegmeier, Frank Aspden, Julie Rio, Donald Harper, J. Wade Elledge, Stephen J. Kirschner, Marc W. Rape, Michael 2024-01-20T19:01:36Z 2024-01-20T19:01:36Z 2021-09-02 2010-07-01 0890-9369 https://pubs.kist.re.kr/handle/201004/131268 The spliceosome, a dynamic assembly of proteins and RNAs, catalyzes the excision of intron sequences from nascent mRNAs. Recent work has suggested that the activity and composition of the spliceosome are regulated by ubiquitination, but the underlying mechanisms have not been elucidated. Here, we report that the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains. The K63-linked chains increase the affinity of Prp3 for the U5 snRNP component Prp8, thereby allowing for the stabilization of the U4/U6.U5 snRNP. Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site. Loss of Usp4 in cells interferes with the accumulation of correctly spliced mRNAs, including those for alpha-tubulin and Bub1, and impairs cell cycle progression. We propose that the reversible ubiquitination of spliceosomal proteins, such as Prp3, guides rearrangements in the composition of the spliceosome at distinct steps of the splicing reaction. English COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT ANAPHASE-PROMOTING COMPLEX RECYCLING FACTOR FACTOR P110 U-BOX RNA PROTEIN DOMAIN PATHWAY DISEASE LIGASES The Prp19 complex and the Usp4(Sart3) deubiquitinating enzyme control reversible ubiquitination at the spliceosome Article 10.1101/gad.1925010 1 GENES & DEVELOPMENT, v.24, no.13, pp.1434 - 1447 GENES & DEVELOPMENT 24 13 1434 1447 scie scopus 000279405000011 2-s2.0-77954523079 Cell Biology Developmental Biology Genetics & Heredity Cell Biology Developmental Biology Genetics & Heredity Article ANAPHASE-PROMOTING COMPLEX RECYCLING FACTOR FACTOR P110 U-BOX RNA PROTEIN DOMAIN PATHWAY DISEASE LIGASES Ubiquitin K63-linked ubiquitin chains splicing Prp19 complex Usp4