Characterization and molecular targeting of CFIm25 (NUDT21/CPSF5) mRNA using miRNAs

dc.contributor.authorKhan, Naazneen
dc.contributor.authorGupta, Mahesh
dc.contributor.authorMasamha, Chioniso Patience
dc.contributor.departmentNeurology, School of Medicine
dc.date.accessioned2025-02-19T10:42:13Z
dc.date.available2025-02-19T10:42:13Z
dc.date.issued2025
dc.description.abstractChanges in protein levels of the mammalian cleavage factor, CFIm25, play a role in regulating pathological processes including neural dysfunction, fibrosis, and tumorigenesis. However, despite these effects, little is known about how CFIm25 (NUDT21) expression is regulated at the RNA level. A potential regulator of NUDT21 mRNA are small non-coding microRNAs (miRNAs). In general, miRNAs bind to the 3'untranslated regions (3'UTRs) and can target the bound mRNA for degradation or inhibit translation thus affecting the levels of protein in cells. Interestingly, a mechanism known as alternative polyadenylation (APA) enables mRNAs to escape miRNA regulation by generating mRNAs with 3'UTRs of different sizes. As many miRNA target sites are located within the 3'UTR, shortening the 3'UTR allows mRNAs to evade miRNAs targeting this region. The differences in the lengths and the sequence composition of the 3'UTRs may also impact the mRNA's translatability and subcellular localization. APA has been reported to regulate over 70% of protein coding genes, thus increasing the transcript repertoire. Several proteins, including mammalian cleavage factor, CFIm25 (NUDT21), have been shown to regulate APA. In this study we wanted to determine whether CFIm25 (NUDT21), itself a regulator of APA, undergoes APA to evade miRNA regulation. We used the blood cancer mantle cell lymphoma (MCL) cells as a model and showed that in these cells, NUDT21 is relatively stable with a long half-life. In addition, the NUDT21 pre-mRNA undergoes alternative APA within the same terminal exon. The three different sized NUDT21 mRNAs have different 3'UTR lengths and they each use a different canonical polyadenylation signal, AAUAAA, for 3'end cleavage and polyadenylation. Use of miRNA mimics and inhibitors showed that miR-23a, miR-222, and miR-323a play a significant role in regulating NUDT21 expression. Hence, these results suggest that NUDT21 mRNA is stable and the different 3'UTRs generated through APA of NUDT21 play an important role in evading miRNA regulation and offers insights into how levels of CFIm25 (NUDT21) may be fine-tuned as needed under different physiological and pathological conditions.
dc.eprint.versionFinal published version
dc.identifier.citationKhan N, Gupta M, Masamha CP. Characterization and molecular targeting of CFIm25 (NUDT21/CPSF5) mRNA using miRNAs. FASEB J. 2025;39(2):e70324. doi:10.1096/fj.202402184R
dc.identifier.urihttps://hdl.handle.net/1805/45816
dc.language.isoen_US
dc.publisherWiley
dc.relation.isversionof10.1096/fj.202402184R
dc.relation.journalThe FASEB Journal
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.sourcePMC
dc.subjectCleavage and polyadenylation specificity factor
dc.subjectMicroRNAs
dc.subjectTumor cell line
dc.titleCharacterization and molecular targeting of CFIm25 (NUDT21/CPSF5) mRNA using miRNAs
dc.typeArticle
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