Abstract

Caenorhabditis elegans 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 C. elegans. Our findings suggest that the exonuclease and helicase domains of human WRN may act in concert to promote RNA-dependent loading into a heterochromatin complex, and the failure of this entire process reduces plasticity in postmitotic neurons.

Highlights

  • Werner syndrome (WS) is an adult-onset progeroid disease in which mutations in the gene encoding the Werner syndrome protein (WRN) are thought to cause abnormal cell function (Shamanna et al, 2017)

  • Two different nematode proteins are orthologous to the functional domains of human WRN: C. elegans MUT-7 contains a 30À50 exonuclease and CeWRN-1 has three helicase domains (Figure 1A)

  • Olfactory behavior is quantified by a chemotaxis index (CI): naıve wild-type animals sense an attractive odor with a high CI value, while prolonged odor stimulation reduces animal odor-seeking behavior, resulting in a decreased CI

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Summary

Introduction

Werner syndrome (WS) is an adult-onset progeroid disease in which mutations in the gene encoding the Werner syndrome protein (WRN) are thought to cause abnormal cell function (Shamanna et al, 2017). In 10–15% of patients diagnosed with WS, no mutation is found within WRN (Oshima and Hisama, 2014) In some of these non-classical cases, an arginine-to-cysteine substitution is found at amino acid 507 (R507C) in the 30À50 exonuclease domain of POLD, which is a DNA polymerase that associates with the WRN helicase during lagging strand synthesis (Lessel et al, 2015). In a Drosophila melanogaster model of WS, loss of the Drosophila WRN, which only contains the 30À50 exonuclease domain, affects lifespan under NAD+ supplementation (Fang et al, 2019). It is unclear how the exonuclease and helicase domains of the WRN differentially contribute to protection against age-related pathologies.

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