biostudies-literatureHsu TYMinistry of Science and Technology, TaiwanNIDCD NIH HHSNINDS NIH HHSNational Institutes of HealthNational Chiao Tung Universitye62449https://www.ebi.ac.uk/biostudies/studies/S-EPMC7946423biostudies-literatureUnknown10<i>Caenorhabditis elegans</i> expresses human Werner syndrome protein (WRN) orthologs as two distinct proteins: MUT-7, with a 3'-5' exonuclease domain, and CeWRN-1, with helicase domains. How these domains cooperate remains unclear. Here, we demonstrate the different contributions of MUT-7 and CeWRN-1 to 22G small interfering RNA (siRNA) synthesis and the plasticity of neuronal signaling. MUT-7 acts specifically in the cytoplasm to promote siRNA biogenesis and in the nucleus to associate with CeWRN-1. The import of siRNA by the nuclear Argonaute NRDE-3 promotes the loading of the heterochromatin-binding protein HP1 homolog HPL-2 onto specific loci. This heterochromatin complex represses the gene expression of the guanylyl cyclase ODR-1 to direct olfactory plasticity in <i>C. elegans</i>. OeLife<i>C. elegans</i> orthologs MUT-7/CeWRN-1 of Werner syndrome protein regulate neuronal plasticity.PMC7946423105-2311-B-009 -002-MY3R01 DC005991The higher education sprout project of the National Chiao Tung University and Ministry of Education, Taiwan103-2311-B-009 -003-MY2R01 NS0875442R01DC005991R01 DC015758Juang BTL'Etoile NDHsu TYZhang Bfalse<i>C. elegans</i> orthologs MUT-7/CeWRN-1 of Werner syndrome protein regulate neuronal plasticity.<i>Caenorhabditis elegans</i> expresses human Werner syndrome protein (WRN) orthologs as two distinct proteins: MUT-7, with a 3'-5' exonuclease domain, and CeWRN-1, with helicase domains. How these domains cooperate remains unclear. Here, we demonstrate the different contributions of MUT-7 and CeWRN-1 to 22G small interfering RNA (siRNA) synthesis and the plasticity of neuronal signaling. MUT-7 acts specifically in the cytoplasm to promote siRNA biogenesis and in the nucleus to associate with CeWRN-1. The import of siRNA by the nuclear Argonaute NRDE-3 promotes the loading of the heterochromatin-binding protein HP1 homolog HPL-2 onto specific loci. This heterochromatin complex represses the gene expression of the guanylyl cyclase ODR-1 to direct olfactory plasticity in <i>C. elegans</i>. O2021-01-01T00:00:00Z2021 Mar2026-05-08T06:10:37.525Z2021-03-16T08:12:40ZS-EPMC79464233364612010.7554/eLife.62449