title: Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures.
abstract: Somatic mutations of pre-mRNA splicing factors recur among patients with myelodysplastic syndrome (MDS) and related malignancies. Although these MDS-relevant mutations alter the splicing of a subset of transcripts, the mechanisms by which these single amino acid substitutions change gene expression remain controversial. New structures of spliceosome intermediates and associated protein complexes shed light on the molecular interactions mediated by 'hotspots' of the SF3B1 and U2AF1 pre-mRNA splicing factors. The frequently mutated SF3B1 residues contact the pre-mRNA splice site. Based on structural homology with other spliceosome subunits, and recent findings of altered RNA binding by mutant U2AF1 proteins, we suggest that affected U2AF1 residues also contact pre-mRNA. Altered pre-mRNA recognition emerges as a molecular theme among MDS-relevant mutations of pre-mRNA splicing factors.
authors.affiliation: Center for RNA Biology and Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Jermaine L
authors.initials: JL
authors.lastname: Jenkins
authors.affiliation: Center for RNA Biology and Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: clara_kielkopf@urmc.rochester.edu.
authors.forename: Clara L
authors.initials: CL
authors.lastname: Kielkopf
mesh_terms: D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors / Q000737:chemistry / Q000235:genetics*; D017381:Spliceosomes / Q000737:chemistry / Q000235:genetics; D000072668:Splicing Factor U2AF / Q000737:chemistry / Q000235:genetics*
chemical_list: D046912:Multiprotein Complexes; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; D000072668:Splicing Factor U2AF
keywords: MDS; SF3B1; U2AF1; cancer; myelodysplastic syndrome; pre-mRNA splicing