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PLoS Genet. 2014 Apr 24;10(4):e1004286. doi: 10.1371/journal.pgen.1004286. eCollection 2014 Apr.

Mutations in conserved residues of the C. elegans microRNA Argonaute ALG-1 identify separable functions in ALG-1 miRISC loading and target repression.

Author information

1
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
2
St-Patrick Research Group in Basic Oncology, Hôtel-Dieu de Québec (Centre Hospitalier Universitaire de Québec), Laval University Cancer Research Centre, Quebec City, Québec, Canada.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.

Abstract

microRNAs function in diverse developmental and physiological processes by regulating target gene expression at the post-transcriptional level. ALG-1 is one of two Caenorhabditis elegans Argonautes (ALG-1 and ALG-2) that together are essential for microRNA biogenesis and function. Here, we report the identification of novel antimorphic (anti) alleles of ALG-1 as suppressors of lin-28(lf) precocious developmental phenotypes. The alg-1(anti) mutations broadly impair the function of many microRNAs and cause dosage-dependent phenotypes that are more severe than the complete loss of ALG-1. ALG-1(anti) mutant proteins are competent for promoting Dicer cleavage of microRNA precursors and for associating with and stabilizing microRNAs. However, our results suggest that ALG-1(anti) proteins may sequester microRNAs in immature and functionally deficient microRNA Induced Silencing Complexes (miRISCs), and hence compete with ALG-2 for access to functional microRNAs. Immunoprecipitation experiments show that ALG-1(anti) proteins display an increased association with Dicer and a decreased association with AIN-1/GW182. These findings suggest that alg-1(anti) mutations impair the ability of ALG-1 miRISC to execute a transition from Dicer-associated microRNA processing to AIN-1/GW182 associated effector function, and indicate an active role for ALG/Argonaute in mediating this transition.

PMID:
24763381
PMCID:
PMC3998888
DOI:
10.1371/journal.pgen.1004286
[Indexed for MEDLINE]
Free PMC Article

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