Abstract
Werner syndrome (WS) is a rare recessive genetic disease characterized by premature aging. Individuals with this disorder develop normally during childhood, but their physiological conditions exacerbate the aging process in late adolescence. WS is caused by mutation of the human WS gene (WRN), which encodes two main domains, a 3′-5′ exonuclease and a 3′-5′ helicase. Caenorhabditis elegans expresses human WRN orthologs as two different proteins: MUT-7, which has a 3′-5′ exonuclease domain, and C. elegans WRN-1 (CeWRN-1), which has only helicase domains. These unique proteins dynamically regulate olfactory memory in C. elegans, providing insight into the molecular roles of WRN domains in humans. In this review, we specifically focus on characterizing the function of MUT-7 in small interfering RNA (siRNA) synthesis in the cytoplasm and the roles of siRNA in directing nuclear CeWRN-1 loading onto a heterochromatin complex to induce negative feedback regulation. Further studies on the different contributions of the 3′-5′ exonuclease and helicase domains in the molecular mechanism will provide clues to the accelerated aging processes in WS.
Highlights
The maintenance of an intact genome is a complex process that depends on the fidelity of DNA replication, DNA secondary structure, and proteins that bind to DNA
These findings support the idea that the 30 -50 exonuclease of MUT-7 is required for small interfering RNA (siRNA) synthesis and suggest that the import of siRNA into the amphid wing C (AWC) neuron nucleus is required for C. elegans WRN-1 (CeWRN-1)-dependent olfactory learning (Figure 3)
There is no cure for this disease, and clinical treatment options for Werner syndrome (WS) only ameliorate symptoms
Summary
The maintenance of an intact genome is a complex process that depends on the fidelity of DNA replication, DNA secondary structure, and proteins that bind to DNA. We summarize some recently obtained comprehensive data showing the ways in which the helicase and exonuclease domains of WRN proteins contribute to different epigenetic regulatory mechanisms in a C. elegans animal model. These data may provide hints at the mechanisms through which siRNA synthesis and heterochromatin modification processes serve as potential determinants of adult-onset WS. Contrast, icase and exonuclease domains of WRN proteins contribute to different epigenetic reguRNA exonucleases play multiple roles in regulating gene expression during the course of latory mechanisms in a C. elegans animal model These data may provide hints at the development or adaptation to environmental changes [21]. Enzyme with DNase and RNase activity will be respectively described
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