title: RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3' UTRs.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Dafne Campigli
authors.initials: DC
authors.lastname: Di Giammartino
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Koichi
authors.initials: K
authors.lastname: Ogami
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Jossie J
authors.initials: JJ
authors.lastname: Yashinskie
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Mainul
authors.initials: M
authors.lastname: Hoque
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA; jlm2@columbia.edu.
authors.forename: James L
authors.initials: JL
authors.lastname: Manley
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D039223:Cleavage And Polyadenylation Specificity Factor / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D026723:Polyadenylation / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D020413:3' Untranslated Regions; D002352:Carrier Proteins; D039223:Cleavage And Polyadenylation Specificity Factor; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C098584:RBBP6 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: AU-rich mRNA; alternative polyadenylation; polyadenylation; pre-mRNA 3′ end processing