Dec 3, 2013

U2AF1 mutations alter splice site recognition in hematological malignancies

BioRxiv : the Preprint Server for Biology
Janine O IlaganRobert K Bradley

Abstract

Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies; however, the molecular consequences of these mutations are unknown. Here, we synthesize patient data, cell culture experiments, and structural modeling to systematically determine how mutations affecting the 3′ splice site recognition factor U2AF1 alter its normal role in RNA splicing in myeloid malignancies. In contrast to initial reports that U2AF1 mutations cause loss of function and global splicing failure, we find that these U2AF1 mutations instead cause gain of function to promote or repress specific variants of the consensus 3′ splice site. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference, which influence the similarity of splicing programs in tumors. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. We created comprehensive global maps of differential splicing driven by each U2AF1 mutation, and use these maps to identify genes that are consistently affected by U2AF1 mutations both in vivo and in cell culture. Many such genes participa...Continue Reading

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Mentioned in this Paper

DNMT3B
U2AF1
Zinc Fingers
In Vivo
Pathogenic Aspects
Biochemical Pathway
DNA Methylation [PE]
Pathogenesis
Hematologic Neoplasms
Genes

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