The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans.
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The primary worm study establishes association of WDR-23 with CUL-4/DDB-1 and regulation of SKN-1 abundance and activity.
"WDR-23, which interacts with the
CUL-4/DDB-1 ubiquitin ligase"
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WDR-23 represses SKN-1 protein level, nuclear accumulation and activity, presumably by targeting it for proteasomal degradation.
"SKN-1 protein levels, nuclear accumulation, and activity are repressed by the WD40 repeat protein WDR-23"
Nuclear and cytoplasmic WDR-23 isoforms mediate differential effects on GEN-1 and SKN-1 substrates.
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Primary worm isoform experiments show that compartment and regulatory outcome cannot be assigned independently of the N terminus.
"These opposing roles are mediated by two distinct isoforms: WDR-23A
in the cytoplasm and WDR-23B in the nucleus."
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The primary study identifies GEN-1 as a WDR-23 substrate; its DNA repair role does not make WDR-23 a nuclease.
"we identify
GEN-1, a Holliday junction resolvase, as an evolutionarily conserved WDR-23
substrate"
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The tested alternative N termini permit GEN-1 interaction, supporting a shared substrate-binding mechanism without establishing localization of the shorter target.
"the N-terminal domain of WDR-23B that mediates nuclear localization does not interfere with binding of GEN-1 in vitro."
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Nuclear WDR-23B inhibits substrates, probably via turnover, whereas cytoplasmic WDR-23A has a proteasome-independent role.
"nuclear WDR-23B inhibits the activity of
substrates, most likely by promoting protein turnover, while cytoplasmic WDR-23A
performs a proteasome-independent role."
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The isoforms differ only at the N terminus, where WDR-23A carries predicted nuclear export signals; S6FN32 lacks this region.
"cytoplasmic WDR-23A is predicted to encode two nuclear export signals (NES) in the N-terminal region that are not found in nuclear WDR-23B."
Regulation of synaptic nlg-1/neuroligin abundance by the skn-1/Nrf stress response pathway protects against oxidative stress.
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In cholinergic motor neurons WDR-23a is punctate in cell bodies and axons, colocalizing with synaptic vesicle and mitochondrial markers, whereas WDR-23b is nuclear.
"a WDR-23a::GFP fusion protein was found in cell bodies and in axons where it adopted a punctate pattern of fluorescence (Figure 1C), whereas WDR-23b::GFP localized exclusively to nuclei"
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WDR-23 controls SKN-1 abundance in neurons as in the intestine.
"suggesting that the primary function of WDR-23 is to negatively regulate SKN-1"
WDR-23 exact-product sequence and repeat conservation
wdr-23 re-review: S6FN32 versus the reviewed WDR-23A/B isoforms
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S6FN32 starts at Met74 of WDR-23A (residue 33 of WDR-23B) and lacks both isoform-specific N termini plus a shared 19-residue segment.
"S6FN32 is therefore an N-terminally shortened alternative gene model of wdr-23 that begins at an internal methionine (Met74 of WDR-23A)."
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Four (W/Y)DxR DDB1-binding-box motifs are retained.
"Four (W/Y)DxR motifs, the DDB1-binding "DxR box" signature of DCAF"
Reproducible comparison against the independently retrieved WDR-23B sequence
UniProt identification of the ribosome-related prediction donor
Frozen exact-input ProtNLM output and UniProt sequence for S6FN32
Falcon deep research report for wdr-23
The Nrf2/SKN-1-dependent glutathione S-transferase π homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of manganism.
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Knockdown of the SKN-1 inhibitor WDR-23 increases resistance to Mn-induced dopamine neuron degeneration
"decreases in gene expression of the SKN-1 inhibitor WDR-23 or the GSTπ-binding cell death activator JNK/JNK-1 result in an increase in resistance to the metal"
WormBase gene description for wdr-23 (worm)