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
Summary
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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