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RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs

Polyadenylation of mRNA precursors is mediated by a large multisubunit protein complex. Here we show that RBBP6 (retinoblastoma-binding protein 6), identified initially as an Rb- and p53-binding protein, is a component of this complex and functions in 3′ processing in vitro and in vivo. RBBP6 associ...

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Autores principales: Di Giammartino, Dafne Campigli, Li, Wencheng, Ogami, Koichi, Yashinskie, Jossie J., Hoque, Mainul, Tian, Bin, Manley, James L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201286/
https://www.ncbi.nlm.nih.gov/pubmed/25319826
http://dx.doi.org/10.1101/gad.245787.114
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author Di Giammartino, Dafne Campigli
Li, Wencheng
Ogami, Koichi
Yashinskie, Jossie J.
Hoque, Mainul
Tian, Bin
Manley, James L.
author_facet Di Giammartino, Dafne Campigli
Li, Wencheng
Ogami, Koichi
Yashinskie, Jossie J.
Hoque, Mainul
Tian, Bin
Manley, James L.
author_sort Di Giammartino, Dafne Campigli
collection PubMed
description Polyadenylation of mRNA precursors is mediated by a large multisubunit protein complex. Here we show that RBBP6 (retinoblastoma-binding protein 6), identified initially as an Rb- and p53-binding protein, is a component of this complex and functions in 3′ processing in vitro and in vivo. RBBP6 associates with other core factors, and this interaction is mediated by an unusual ubiquitin-like domain, DWNN (“domain with no name”), that is required for 3′ processing activity. The DWNN is also expressed, via alternative RNA processing, as a small single-domain protein (isoform 3 [iso3]). Importantly, we show that iso3, known to be down-regulated in several cancers, competes with RBBP6 for binding to the core machinery, thereby inhibiting 3′ processing. Genome-wide analyses following RBBP6 knockdown revealed decreased transcript levels, especially of mRNAs with AU-rich 3′ untranslated regions (UTRs) such as c-Fos and c-Jun, and increased usage of distal poly(A) sites. Our results implicate RBBP6 and iso3 as novel regulators of 3′ processing, especially of RNAs with AU-rich 3′ UTRs.
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spelling pubmed-42012862015-04-15 RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs Di Giammartino, Dafne Campigli Li, Wencheng Ogami, Koichi Yashinskie, Jossie J. Hoque, Mainul Tian, Bin Manley, James L. Genes Dev Research Paper Polyadenylation of mRNA precursors is mediated by a large multisubunit protein complex. Here we show that RBBP6 (retinoblastoma-binding protein 6), identified initially as an Rb- and p53-binding protein, is a component of this complex and functions in 3′ processing in vitro and in vivo. RBBP6 associates with other core factors, and this interaction is mediated by an unusual ubiquitin-like domain, DWNN (“domain with no name”), that is required for 3′ processing activity. The DWNN is also expressed, via alternative RNA processing, as a small single-domain protein (isoform 3 [iso3]). Importantly, we show that iso3, known to be down-regulated in several cancers, competes with RBBP6 for binding to the core machinery, thereby inhibiting 3′ processing. Genome-wide analyses following RBBP6 knockdown revealed decreased transcript levels, especially of mRNAs with AU-rich 3′ untranslated regions (UTRs) such as c-Fos and c-Jun, and increased usage of distal poly(A) sites. Our results implicate RBBP6 and iso3 as novel regulators of 3′ processing, especially of RNAs with AU-rich 3′ UTRs. Cold Spring Harbor Laboratory Press 2014-10-15 /pmc/articles/PMC4201286/ /pubmed/25319826 http://dx.doi.org/10.1101/gad.245787.114 Text en © 2014 Di Giammartino et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six 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/.
spellingShingle Research Paper
Di Giammartino, Dafne Campigli
Li, Wencheng
Ogami, Koichi
Yashinskie, Jossie J.
Hoque, Mainul
Tian, Bin
Manley, James L.
RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs
title RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs
title_full RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs
title_fullStr RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs
title_full_unstemmed RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs
title_short RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs
title_sort rbbp6 isoforms regulate the human polyadenylation machinery and modulate expression of mrnas with au-rich 3′ utrs
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201286/
https://www.ncbi.nlm.nih.gov/pubmed/25319826
http://dx.doi.org/10.1101/gad.245787.114
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