RESUMO
Recurrent mutations in the spliceosome are observed in several human cancers, but their functional and therapeutic significance remains elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3' splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3' ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3' ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer.
Assuntos
Processamento Alternativo , Mutação , Neoplasias/genética , Fosfoproteínas/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Alelos , Sequência de Aminoácidos , Sequência de Bases , Células HEK293 , Humanos , Dados de Sequência Molecular , Taxa de Mutação , Degradação do RNAm Mediada por Códon sem Sentido , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Fatores de Processamento de RNA , Ribonucleoproteína Nuclear Pequena U2/química , Ribonucleoproteína Nuclear Pequena U2/metabolismoRESUMO
A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/química , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos de Epóxi/síntese química , Compostos de Epóxi/metabolismo , Macrolídeos/síntese química , Macrolídeos/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/química , Splicing de RNA/efeitos dos fármacos , Ribonucleoproteína Nuclear Pequena U2/antagonistas & inibidores , Ribonucleoproteína Nuclear Pequena U2/química , Antineoplásicos/química , Sítios de Ligação , Compostos de Epóxi/química , Humanos , Macrolídeos/química , Fatores de Processamento de RNARESUMO
The total synthesis of kalihinol C, a bis-isonitrile marine diterpenoid isolated from Acanthella sp., is reported. The decalin framework was established via an intramolecular Diels-Alder cycloaddition and subsequently functionalized through a series of substrate-controlled diastereoselective transformations to install the tertiary isonitrile, beta-hydroxy isonitrile, and pendant tetrahydrofuranyl ring.
