DRE-1: An Evolutionarily Conserved F Box Protein that Regulates C. elegans Developmental Age

Abstract

During metazoan development, cells acquire both positional and temporal identities. The Caenorhabditis elegans heterochronic loci are global regulators of larval temporal fates. Most encode conserved transcriptional and translational factors, which affect stage-appropriate programs in various tissues. Here, we describe dre-1, a heterochronic gene, whose mutant phenotypes include precocious terminal differentiation of epidermal stem cells and altered temporal patterning of gonadal outgrowth. Genetic interactions with other heterochronic loci place dre-1 in the larval-to-adult switch. dre-1 encodes a highly conserved F box protein, suggesting a role in an SCF ubiquitin ligase complex. Accordingly, RNAi knockdown of the C. elegans SKP1-like homolog SKR-1, the cullin CUL-1, and ring finger RBX homologs yielded similar heterochronic phenotypes. DRE-1 and SKR-1 form a complex, as do the human orthologs, hFBXO11 and SKP1, revealing a phyletically ancient interaction. The identification of core components involved in SCF-mediated modification and/or proteolysis suggests an important level of regulation in the heterochronic hierarchy.

Human protein arginine methyltransferases in vivo – distinct properties of eight canonical members of the PRMT family

“…Unlike the canonical PRMTs, FBOX11 is not a member of the seven-β-strand methyltransferase family. In addition, no methyltransferase activity was reported for the human or worm FBOX11 proteins (Fielenbach et al, 2007). Consequently, further work is needed to determine whether FBXO11 is a PRMT, and we have not studied it the context of this article.…”

Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma

“…dre-1 is predicted to encode an F-box domain protein and was previously identified as a gene affecting developmental timing (13). However, neither animals carrying mutations in timing genes nor animals containing mutations in known DRE-1 interacting proteins (17) had tail-spike cell survival defects (Table S2).…”

Regulation of TGF-β signaling, exit from the cell cycle, and cellular migration through cullin cross-regulation: SCF-FBXO11 turns off CRL4-Cdt2

“…Partial loss of function mutations in dre-1 cause precocious fusion of seam cells, altered temporal patterning of gonadal outgrowths, and gaps in the adult alae. 50 The latter phenotype results from failure to exit the cell cycle and differentiate properly. 40,52 Importantly, the knockdown of cdt-2 (the worm ortholog of Cdt2) by si-RNA reduced the number of dre-1 (dh99) mutant animals with alae gaps from 56-13%, demonstrating that the alae gaps were due to the accumulation of Cdt2 following the genetic inactivation of DRE-1.…”

“…40 Deletion of FBXO11 in C. elegans (DRE-1) or in mice results in lethality. 50,51 During development, epidermal stem cells (seam cels) in the worm undergo multiple rounds of asymmetric cell division before they exit the cell cycle early in L4 and fuse into long syncytium, forming a continuous ridged cuticular structure known as adult alae. Partial loss of function mutations in dre-1 cause precocious fusion of seam cells, altered temporal patterning of gonadal outgrowths, and gaps in the adult alae.…”