On the rules of engagement for microRNAs targeting protein coding regions

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dc.contributor.authorSapkota, S.
dc.contributor.authorPillman, K.A.
dc.contributor.authorDredge, B.K.
dc.contributor.authorLiu, D.
dc.contributor.authorBracken, J.M.
dc.contributor.authorKachooei, S.A.
dc.contributor.authorChereda, B.
dc.contributor.authorGregory, P.A.
dc.contributor.authorBracken, C.P.
dc.contributor.authorGoodall, G.J.
dc.date.issued2023
dc.descriptionPublished online 31 July 2023
dc.description.abstractMiRNAs post-transcriptionally repress gene expression by binding to mRNA 3 UTRs, but the extent to which they act through protein coding regions (CDS regions) is less well established. MiRNA interaction studies show a substantial proportion of binding occurs in CDS regions, however sequencing studies show much weaker effects on mRNA levels than from 3 UTR interactions, presumably due to competition from the translating ribosome. Consequently, most target prediction algorithms consider only 3 UTR interactions. However, the consequences of CDS interactions may have been underestimated, with the reporting of a novel mode of miRNA-CDS interaction requiring base pairing of the miRNA 3 end, but not the canonical seed site, leading to repression of translation with little effect on mRNA turnover. Using extensive reporter, western blotting and bioinformatic analyses, we confirm that miRNAs can indeed suppress genes through CDS-interaction in special circumstances. However, in contrast to that previously reported, we find repression requires extensive base-pairing, including of the canonical seed, but does not strictly require base pairing of the 3 miRNA terminus and is mediated through reducing mRNA levels. We conclude that suppression of endogenous genes can occur through miRNAs binding to CDS, but the requirement for extensive basepairing likely limits the regulatory impacts to modest effects on a small subset of targets.
dc.description.statementofresponsibilitySunil Sapkota, Katherine A. Pillman, B. Kate Dredge, Dawei Liu, Julie M. Bracken, Saba Ataei Kachooei, Bradley Chereda, Philip A. Gregory, Cameron P. Bracken, and Gregory J. Goodall
dc.identifier.citationNucleic Acids Research, 2023; 51(18):9938-9951
dc.identifier.doi10.1093/nar/gkad645
dc.identifier.issn0305-1048
dc.identifier.issn1362-4962
dc.identifier.orcidPillman, K.A. [0000-0002-5869-889X]
dc.identifier.orcidDredge, B.K. [0000-0002-6103-5165]
dc.identifier.orcidLiu, D. [0000-0003-4592-8358]
dc.identifier.orcidGregory, P.A. [0000-0002-0999-0632]
dc.identifier.orcidGoodall, G.J. [0000-0003-1294-0692]
dc.identifier.urihttps://hdl.handle.net/2440/139193
dc.language.isoen
dc.publisherOxford University Press
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1188274
dc.relation.granthttp://purl.org/au-research/grants/arc/DP190103333
dc.rights© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.source.urihttps://doi.org/10.1093/nar/gkad645
dc.titleOn the rules of engagement for microRNAs targeting protein coding regions
dc.typeJournal article
pubs.publication-statusPublished

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