Author ORCID Identifier
Date of Graduation
Genes and Development
Doctor of Philosophy (PhD)
Altered DICER1 protein levels are associated with developmental disorders, infertility, macular degenerative blindness, aging, and cancer in humans. Recently, post-translational regulation of Dicer1 via phosphorylation has been described in C. elegans. Oscillation of Dicer1 phosphorylation to regulate its activity is essential for germ cell development and embryogenesis in worms. These observations led us to posit that Dicer1 protein levels and activity are under tight regulation for normal mammalian homeostasis. To test whether phosphorylation of Dicer1 regulates its activity in mammals, I generated phospho-mimetic knock-in mouse models by replacing Serines 1712 and 1836 with Aspartic acids individually or together (dual phosphorylation). Dicer1 functions are impaired by phosphorylation at Ser1836, and further augmented by Ser1712 phosphorylation. Constitutive Dicer1 phosphorylation at Ser1836 leads to highly penetrant post-natal lethality, and accelerates aging and causes infertility in survivors. Homozygosity of dual phosphorylated Dicer1 leads to a hypermetabolic phenotype in MEFs and mice, while heterozygosity is sufficient to promote tumor development and dissemination in two independent tumor models. I have identified a phospho-Dicer1 specific miRNA signature that is strongly associated with metabolic and oncogenic pathways. These data identify constitutive phosphorylation of Dicer1 as a driver of pathologies in mammals, with the phenotypes in mice resembling the spectrum of human diseases associated with dysregulated DICER1.
Dicer, miRNA, Phosphorylation, ERK, KRas, p53, Aging, Cancer, Metabolism