Structure-Specific Cleavage of an RNA Repeat Expansion with a Dimeric Small Molecule Is Advantageous over Sequence-Specific Recognition by an Oligonucleotide.

ABSTRACT: Myotonic dystrophy type 2 (DM2) is a genetically defined muscular dystrophy that is caused by an expanded repeat of r(CCUG) [r(CCUG)^exp] in intron 1 of a CHC-type zinc finger nucleic acid binding protein (CNBP) pre-mRNA. Various mechanisms contribute to DM2 pathology including pre-mRNA splicing defects caused by sequestration of the RNA splicing regulator muscleblind-like-1 (MBNL1) by r(CCUG)^exp. Herein, we study the biological impacts of the molecular recognition of r(CCUG)^exp's structure by a designer dimeric small molecule that directly cleaves the RNA in patient-derived cells. The compound is comprised of two RNA-binding modules conjugated to a derivative of the natural product bleomycin. Careful design of the chimera affords RNA-specific cleavag

SUBMITTER: Benhamou RI 

PROVIDER: S-EPMC7081929 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature