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. 2011 Sep 1;7(9):e1002235. doi: 10.1371/journal.pgen.1002235

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Rizki et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

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We propose that C. elegans HCF-1 and SIR-2.1 coordinate to fine-tune the transcriptional activity of DAF-16 on a distinct subset of potential target genes. DAF-16 target genes responsive to the hcf-1/sir-2.1 pathway largely overlap with a small subset of IIS-regulated genes, and are specialized in longevity determination, cellular defense, and lipid/fatty acid/amino acid homeostasis. HCF-1 likely represses DAF-16 by forming a complex with SIR-2.1 and 14-3-3, and antagonizing their abilities to stimulate DAF-16. This functional relationship is highly conserved as mammalian HCF proteins also repress the expression of multiple FOXO/SIRT1 target genes and reside in protein complexes with SIRT1 and FOXO3. Our results highlight HCF proteins to be key components of the regulatory network linking SIR-2.1/SIRT1 and DAF-16/FOXO in diverse organisms.