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Ref Type Journal Article
PMID (28541300)
Authors Teng T, Tsai JH, Puyang X, Seiler M, Peng S, Prajapati S, Aird D, Buonamici S, Caleb B, Chan B, Corson L, Feala J, Fekkes P, Gerard B, Karr C, Korpal M, Liu X, T Lowe J, Mizui Y, Palacino J, Park E, Smith PG, Subramanian V, Wu ZJ, Zou J, Yu L, Chicas A, Warmuth M, Larsen N, Zhu P
Title Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A-SF3b complex.
Journal Nature communications
Vol 8
Issue
Date 2017 05 25
URL
Abstract Text Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site. RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators. Moreover, PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons. We determine the crystal structure of human PHF5A demonstrating that Y36 is located on a highly conserved surface. Analysis of the cryo-EM spliceosome Bact complex shows that the resistance mutations cluster in a pocket surrounding the branch point adenosine, suggesting a competitive mode of action. Collectively, we propose that PHF5A-SF3B1 forms a central node for binding to these splicing modulators.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
SF3B1 R1074H missense unknown SF3B1 R1074H lies within HEAT repeat 9 of the Sf3b1 protein (UniProt.org). R1074H has been demonstrated to mediate resistance to splicing modulators in culture (PMID: 28541300, PMID: 21981285, PMID: 29491137), but has not been biochemically characterized and therefore, its effect on Sf3b1 protein function is unknown. Y
SF3B1 V1078A missense unknown SF3B1 V1078A lies within HEAT repeat 9 of the Sf3b1 protein (UniProt.org). V1078A has been demonstrated to mediate resistance to splicing modulators in culture (PMID: 28541300, PMID: 21981285), but has not been biochemically characterized and therefore, its effect on Sf3b1 protein function is unknown. Y
SF3B1 V1078I missense unknown SF3B1 V1078I lies within HEAT repeat 9 of the Sf3b1 protein (UniProt.org). V1078I has been demonstrated to mediate resistance to splicing modulators in culture (PMID: 21981285, PMID: 28541300), but has not been biochemically characterized and therefore, its effect on Sf3b1 protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SF3B1 R1074H colorectal cancer resistant E7107 Preclinical - Cell culture Actionable In a preclinical study, SF3B1 R1074H was identified as a recurrent mutation in colorectal cancer cells acquired resistance to E7107 in culture (PMID: 28541300). 28541300
SF3B1 V1078A colorectal cancer resistant E7107 Preclinical - Cell culture Actionable In a preclinical study, SF3B1 V1078A was identified as a recurrent mutation in colorectal cancer cells acquired resistance to E7107 in culture (PMID: 28541300). 28541300
SF3B1 V1078I colorectal cancer resistant E7107 Preclinical - Cell culture Actionable In a preclinical study, SF3B1 V1078I was identified as a recurrent mutation in colorectal cancer cells acquired resistance to E7107 in culture (PMID: 28541300). 28541300