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Oppositional poly(A) tail length regulation by FMRP and CPEB1

Shin, Jihae
Paek, Ki Young
Chikhaoui, Lies
Jung, Suna
Ponny, SitharaRaju
Suzuki, Yutaka
Padmanabhan, Kiran
Richter, Joel D
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Abstract

Poly(A) tail length is regulated in both the nucleus and cytoplasm. One factor that controls polyadenylation in the cytoplasm is CPEB1, an RNA binding protein that associates with specific mRNA 3'UTR sequences to tether enzymes that add and remove poly(A). Two of these enzymes, the noncanonical poly(A) polymerases GLD2 (TENT2, PAPD4, Wispy) and GLD4 (TENT4B, PAPD5, TRF4, TUT3), interact with CPEB1 to extend poly(A). To identify additional RNA binding proteins that might anchor GLD4 to RNA, we expressed double tagged GLD4 in U87MG cells, which was used for sequential immunoprecipitation and elution followed by mass spectrometry. We identified several RNA binding proteins that coprecipitated with GLD4, among which was FMRP. To assess whether FMRP regulates polyadenylation, we performed TAIL-seq from WT and FMRP-deficient HEK293 cells. Surprisingly, loss of FMRP resulted in an overall increase in poly(A), which was also observed for several specific mRNAs. Conversely, loss of CPEB1 elicited an expected decrease in poly(A), which was examined in cultured neurons. We also examined polyadenylation in wild type (WT) and FMRP-deficient mouse brain cortex by direct RNA nanopore sequencing, which identified RNAs with both increased and decreased poly(A). Our data show that FMRP has a role in mediating poly(A) tail length, which adds to its repertoire of RNA regulation.

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Shin J, Paek KY, Chikhaoui L, Jung S, Ponny S, Suzuki Y, Padmanabhan K, Richter JD. Oppositional poly(A) tail length regulation by FMRP and CPEB1. RNA. 2022 May;28(5):756-765. doi: 10.1261/rna.079050.121. Epub 2022 Feb 25. PMID: 35217597; PMCID: PMC9014880.

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10.1261/rna.079050.121
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35217597
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Copyright © 2022 Shin et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society. This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.; Attribution-NonCommercial 4.0 International