XRN2 Autoregulation and Control of Polycistronic Gene Expresssion in Caenorhabditis elegans

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Abstract
XRN2 is a conserved 5’→3’ exoribonuclease that complexes with proteins that contain XRN2-binding domains (XTBDs). In Caenorhabditis elegans (C. elegans), the XTBD-protein PAXT-1 stabilizes XRN2 to retain its activity. XRN2 activity is also promoted by 3'(2'),5'-bisphosphate nucleotidase 1 (BPNT1) through hydrolysis of an endogenous XRN inhibitor 3’-phosphoadenosine-5'-phosphate (PAP). Here, we find through unbiased screening that loss of bpnt-1 function suppresses lethality caused by paxt-1 deletion. This unexpected finding is explained by XRN2 autoregulation, which occurs through repression of a cryptic promoter activity and destabilization of the xrn-2 transcript. De-repression appears to be triggered such that more robust XRN2 perturbation, by elimination of both PAXT-1 and BPNT1, is less detrimental to worm viability than absence of PAXT-1 alone. Indeed, we find that two distinct XRN2 repression mechanisms are alleviated at different thresholds of XRN2 inactivation. Like more than 15% of C. elegans genes, xrn-2 occurs in an operon, and we identify additional operons under its control, consistent with a broader function of XRN2 in polycistronic gene regulation. Regulation occurs through intercistronic regions that link genes in an operon, but a part of the mechanisms may allow XRN2 to operate on monocistronic genes in organisms lacking operons. XRN2 is a conserved eukaryotic protein that controls gene expression by degrading or processing various types of RNA. Here we find that XRN2 negatively regulates its own levels in the nematode C. elegans. In response to reduction of XRN2 activity, this self-repression is alleviated, increasing xrn-2 mRNA and thus protein production, which restores robust XRN2 activity. Although XRN2 and its upstream gene are transcribed from a single promoter as a gene expression unit called “operon”, XRN2 regulates only itself. It does so by inactivating a cryptic promoter that exists between the two genes and by destabilizing its own nascent transcript. Many other C. elegans genes (>15%) occur in operons, and we identify additional operons that XRN2 regulates through an analogous mechanism. Thus we find a novel function of XRN2 in modulating expression of genes in operons including itself. As one of the mechanisms could operate on genes outside operons, XRN2 may also regulate gene expression in organisms lacking operonic gene organization.
Funding Information
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_143313)
  • Novartis Stiftung für Medizinisch-Biologische Forschung (CH) (NA)

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