RT Journal Article
SR Electronic
T1 Interaction of modified oligonucleotides with nuclear proteins, formation of novel nuclear structures and sequence-independent effects on RNA processing
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 446773
DO 10.1101/446773
A1 Loren L Flynn
A1 Ruohan Li
A1 May T Aung-Htut
A1 Ianthe L Pitout
A1 Jack A L Cooper
A1 Alysia Hubbard
A1 Lisa Griffiths
A1 Charlie Bond
A1 Steve D Wilton
A1 Archa H Fox
A1 Sue Fletcher
YR 2019
UL http://biorxiv.org/content/early/2019/01/08/446773.abstract
AB Oligonucleotides and nucleic acid analogues that alter gene expression are showing therapeutic promise for selected human diseases. The modification of synthetic nucleic acids to protect against nuclease degradation and to influence drug function is common practice, however, such modifications may also confer unexpected physicochemical and biological properties. Here we report backbone-specific effects of modified oligonucleotides on subnuclear organelles, altered distribution of nuclear proteins, the appearance of novel structured nuclear inclusions, and modification of RNA processing in cultured cells transfected with antisense oligonucleotides on a phosphorothioate backbone. Phosphodiester and phosphorodiamidate morpholino oligomers elicited no such consequences. Disruption of subnuclear structures and proteins elicit severe phenotypic disturbances, revealed by transcriptomic analysis of fibroblasts exhibiting such disruption. These data suggest that the toxic effects and adverse events reported after clinical evaluation of phosphorothioate nucleic acid drugs may be mediated, at least in part, by non-specific interaction of nuclear components with the phosphorothioate backbone.AbbreviationsAOantisense oligonucleotideSMAspinal muscular atrophyDMDDuchenne muscular dystrophyPMOphosphorodiamidate morpholino oligomerALSamyotrophic lateral sclerosis