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The NineTeen Complex (NTC) and NTC-associated proteins as targets for spliceosomal ATPase action during pre-mRNA splicing.

ABSTRACT: Pre-mRNA splicing is an essential step in gene expression that removes intron sequences efficiently and accurately to produce a mature mRNA for translation. It is the large and dynamic RNA-protein complex called the spliceosome that catalyzes intron removal. To carry out splicing the spliceosome not only needs to assemble correctly with the pre-mRNA but the spliceosome requires extensive remodelling of its RNA and protein components to execute the 2 steps of intron removal. Spliceosome remodelling is achieved through the action of ATPases that target both RNA and proteins to produce spliceosome conformations competent for each step of spliceosome activation, catalysis and disassembly. An increasing amount of research has pointed to the spliceosome associated NineTeen Complex (NTC) of proteins as targets for the action of a number of the spliceosomal ATPases during spliceosome remodelling. In this point-of-view article we present the latest findings on the changes in the NTC that occur following ATPase action that are required for spliceosome activation, catalysis and disassembly. We proposed that the NTC is one of the main targets of ATPase action during spliceosome remodelling required for pre-mRNA splicing.

SUBMITTER: de Almeida RA

PROVIDER: S-EPMC4615276 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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SUMO conjugation to spliceosomal proteins is required for efficient pre-mRNA splicing.

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Project description:Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

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