Short interspersed nuclear element (SINE)-mediated post-transcriptional effects on human and mouse gene expression: SINE-UP for active duty

Abstract

Primate-specific Alu short interspersed nuclear elements (SINEs) and rodent-specific B and ID (B/ID) SINEs are non-autonomous and generally non-coding retrotransposons that have been copied and pasted into the respective genomes so as to constitute what is estimated to be a remarkable 13% and 8% of those genomes. In the context of messenger RNAs (mRNAs), those residing within 3'-untranslated regions (3'UTRs) can influence mRNA export from the nucleus to the cytoplasm, mRNA translation and/or mRNA decay via proteins with which they associate either individually or base-paired in cis or in trans with a partially complementary SINE. Each of these influences impinges on the primary function of mRNA, which is to serve as a template for protein synthesis. This review describes how human cells have used 3'UTR Alu elements to mediate post-transcriptional gene regulation and also describes examples of convergent evolution between human and mouse 3'UTR SINEs. This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'.

Keywords: 3′-untranslated regions; double-stranded RNA-binding proteins; mRNA export; mRNA translation, mRNA decay; short interspersed elements.

Figure 1.

Intermolecular base-pairing via partially complementary SINEs can create Staufen (STAU)-binding sites that trigger STAU-mediated mRNA decay (SMD). (a) Base-pairing between the 3′UTR SINE of a translationally active mRNA and a partially complementary SINE of another translationally inactive RNA (either a lncRNA or a translationally inactive mRNA) can trigger the SMD of the translationally active mRNA. (b) Base-pairing between the 3′UTR SINEs of two translationally active mRNAs can trigger the SMD of both mRNAs. (Online version in colour.)

Figure 2.

3′UTR IRAlus can regulate mRNA localization, mRNA translation and mRNA decay within cells. (a) Staufen (STAU) binding to 3′UTR IRAlus can enhance 3′UTR IRAlus gene expression by two consecutive mechanisms. In the first, STAU binding in the nucleus inhibits binding by the paraspeckle constituent p54nrb, thereby preventing 3′UTR IRAlus mRNA retention in nuclear paraspeckles via the lncRNA NEAT1 and allowing export to the cytoplasm. In the second, once in the cytoplasm, STAU binding to 3′UTR IRAlus inhibits binding by the translational repressor protein kinase R (PKR) binding, thereby preventing PKR activation and allowing translation not only of the 3′UTR IRAlus mRNA but also of all of the cellular mRNAs (details provided in Elbarbary et al. [36]). (b) Cellular stress, including ultraviolet irradiation or heat shock, activate the MKK6–p38–mitogen and stress-activated protein kinase (MSK)1/2 signalling cascade so that MSK1 and MSK2 phosphorylate nuclear ADAR1p110 (details provided in Sakurai et al. [37]). Phosphorylated ADAR1p110 then binds Exportin 5 and is exported to the cytoplasm. Once in the cytoplasm, ADAR1p110 binding to 3′UTR IRAlus inhibits STAU binding, thereby preventing the SMD of 3′UTR IRAlus mRNAs, a number of which encode anti-apoptotic proteins that promote the survival of stressed cells. (Online version in colour.)