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.
Highlights
Polycistronic gene expression is common in prokaryotes: multiple genes are arranged tandemly and transcribed from a single promoter, as one RNA precursor
Many other C. elegans genes (>15%) occur in operons, and we identify additional operons that XRN2 regulates through an analogous mechanism
We have recently reported that XRN2 is stabilized by forming a complex with PAXT-1 in C. elegans [23, 24]. paxt-1 null (paxt-1(0)) animals cannot survive at temperatures ! 26°C due to degradation of XRN2
Summary
Polycistronic gene expression is common in prokaryotes: multiple genes are arranged tandemly and transcribed from a single promoter, as one RNA precursor This organization of genes into an operon permits regulation of functionally related genes in one unit. The polycistronic transcript is the template for protein synthesis in prokaryotes, the individual cistrons in C. elegans are separated prior to translation, in the nucleus, by a process termed trans-splicing [7, 8] This process is mechanistically similar to cis-splicing, which uses the spliceosome to excise the introns and fuse the exons of eukaryotic pre-mRNAs. rather than joining two fragments of the same precursor, it links a 5’-capped, 22-nucleotide RNA sequence, the splice-leader (SL), which is transcribed separately, to a splice acceptor site on the nascent transcript. For downstream genes in operons, trans-splicing occurs subsequent to cleavage of the immediately upstream premRNA at the 3’ end [7, 8]
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