RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 39 UTRs

Dafne Campigli Di Giammartino, Wencheng Li, Koichi Ogami, Jossie J. Yashinskie, Mainul Hoque, Bin Tian, James L. Manley

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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 39 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 39 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 39 processing. Genome-wide analyses following RBBP6 knockdown revealed decreased transcript levels, especially of mRNAs with AU-rich 39 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 39 processing, especially of RNAs with AU-rich 39 UTRs.

Original languageEnglish (US)
Pages (from-to)2248-2260
Number of pages13
JournalGenes and Development
Volume28
Issue number20
DOIs
StatePublished - Oct 15 2014

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • AU-rich mRNA
  • Alternative polyadenylation
  • Polyadenylation
  • pre-mRNA 39 end processing

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