Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures

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...

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Bibliographic Details
Published in:Trends in genetics 2017-05, Vol.33 (5), p.336-348
Main Authors: Jenkins, Jermaine L, Kielkopf, Clara L
Format: Article
Language:English
Subjects:
cancer
Humans
MDS
Medical Education
Multiprotein Complexes - chemistry
Multiprotein Complexes - genetics
Mutation
myelodysplastic syndrome
Myelodysplastic Syndromes - genetics
Myelodysplastic Syndromes - pathology
Phosphoproteins - chemistry
Phosphoproteins - genetics
pre-mRNA splicing
RNA Splicing - genetics
RNA Splicing Factors - chemistry
RNA Splicing Factors - genetics
SF3B1
Spliceosomes - chemistry
Spliceosomes - genetics
Splicing Factor U2AF - chemistry
Splicing Factor U2AF - genetics
U2AF1
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Summary: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.
ISSN:0168-9525
DOI:10.1016/j.tig.2017.03.001