![]() Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown and evolutionarily conserved sequence-specificity of the mRNA 3′ processing machinery. As the Compound 2-resistant CS sequences, characterized by U/A-rich motifs, are prevalent in PASs from yeast to human, the CS region sequence may have more fundamental functions beyond determining drug resistance. ![]() ![]() Once an mRNA has been produced, by transcription and processing the information present in its nucleotide sequence is used to synthesize a protein. We propose a biochemical model in which CPSF73 and other mRNA 3′ processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. An mRNA Sequence Is Decoded in Sets of Three Nucleotides. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. Although CPSF73 is universally required for mRNA 3′ end formation, we have unexpectedly found that Compound 2- mediated inhibition of pre-mRNA 3′ processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3′ processing. JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities.
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