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Resources » Paper

Burger, Julien et al. (2009) International Worm Meeting "Functional characterization of a novel cullin-based E3-ligase involved in cell cycle progression in C. elegans."

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  • Comments on Burger, Julien et al. (2009) International Worm Meeting "Functional characterization of a novel cullin-based E3-ligase involved in cell cycle progression in C. elegans." (0)

  • Overview

    Status:
    Publication type:
    Meeting_abstract
    WormBase ID:
    WBPaper00033568

    Burger, Julien, Merlet, Jorge, Richaudeau, Benedicte, & Pintard, Lionel (2009). Functional characterization of a novel cullin-based E3-ligase involved in cell cycle progression in C. elegans presented in International Worm Meeting. Unpublished information; cite only with author permission.

    The COP9 signalosome (CSN) is an evolutionary conserved macromolecular complex that interacts with Cullin-RING ubiquitin-Ligases (CRLs) and regulates their activity by hydrolyzing cullin-Nedd8 conjugates. In particular, the CSN sequesters inactive CRL4Ddb2 ubiquitin-ligase, which rapidly dissociates from the CSN upon DNA damage. Whether other CRLs are similarly sequestered and regulated by the CSN is currently unknown. We have recently defined the protein interaction network of the mammalian CSN using a combination of affinity purification tagging and sensitive tandem mass spectrometry approaches (LC-MS/MS). Notably we identified a small subset of CRLs, which stably interact with the CSN, and thus might be specifically activated by dissociation from the CSN in response to specific cues, such as DNA damage. Consistent with this hypothesis, most of the CSN-interacting CRLs identified in this study appear to be involved in cell cycle progression and DNA metabolism; however, the function of others remains elusive. We have identified worm orthologues of most of these CRLs and we are now using C. elegans as a model system to dissect their function during cell cycle progression. In particular, we are currently focusing on a CUL-2-based ubiquitin-ligase that uses F33G12.4/LRR-1 as a substrate-recognition subunit. LRR-1 contains a typical BC/CUL-2 box and binds CRL2 components in vitro and in vivo. RNAi-mediated depletion of lrr-1 results in an embryonic lethal phenotype, with severe delays in S-phase, as revealed by time-lapse video-microscopy. Importantly, this delay is entirely suppressed by inactivation of the DNA replication checkpoint, suggesting that the CRL2LRR-1 complex might control DNA replication in the early embryo. Consistent with this hypothesis, lrr-1(RNAi) treated embryos are hypersensitive to sublethal doses of the replication inhibitor hydroxyurea (HU) and the DNA-damaging agent methyl methanesulfonate (MMS). Experiments are under way to elucidate the function of this ubiquitin-ligase and to identify its critical substrate(s).


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