DET1

Last update 08 May 2025

Basic Info

Synonyms

De-etiolated-1 homolog, DET1, DET1 homolog

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Introduction

Component of the E3 ubiquitin ligase DCX DET1-COP1 complex, which is required for ubiquitination and subsequent degradation of target proteins. The complex is involved in JUN ubiquitination and degradation.

100 Clinical Results associated with DET1

100 Translational Medicine associated with DET1

0 Patents (Medical) associated with DET1

132

Literatures (Medical) associated with DET1

15 Apr 2025·Proceedings of the National Academy of Sciences

Correction to Supporting Information for Karayel et al., Impairment of DET1 causes neurological defects and lethality in mice and humans

Article

28 Feb 2025·Science Advances

DET1 dynamics underlie cooperative ubiquitination by CRL4 ^DET1-COP1 complexes

Article

Author: Brown, Simon H. J. ; Mace, Peter D. ; Filipcik, Pavel ; Curry, Jack R. ; Nyvall, Hunter G. ; Turk, Liam S. ; Jamieson, Sam A. ; Burke, John E. ; Loughran, Tarren A. ; Burgess, Abigail E. ; Dunlop, Jessica L.

Transcription factor ubiquitination is a decisive regulator of growth and development. The DET1-DDB1-DDA1 (DDD) complex associates with the Cullin-4 ubiquitin ligase (CRL4) and a second ubiquitin ligase, COP1, to control ubiquitination of transcription factors involved in neurological, metabolic, and immune cell development. Here, we report the structure of the human DDD complex, revealing a specific segment of DET1 that can recruit ubiquitin-conjugating (E2) enzymes. Structural variability analysis, mass spectrometry, and mutagenesis based on AlphaFold predictions suggest that dynamic closure of DET1, stabilized by DDA1, underlies coordinated recruitment of E2 enzymes and COP1. Biochemical assays suggest that the E2 acts as a recruitment factor to bring COP1 to DET1 for more effective substrate ubiquitination, which parallels a catalytically inactive E2 enzyme (COP10) in plant DDD complexes. This work provides a clear architecture for regulation and cooperative CRL4 DET1-COP1 complex assembly, which can affect degradation of diverse targets by COP1 complexes.

18 Feb 2025·Proceedings of the National Academy of Sciences

Impairment of DET1 causes neurological defects and lethality in mice and humans

Article

Author: Anand, Dhullipala ; Karayel, Ozge ; Klaeger, Susan ; Soung, Allison ; Harris, Seth F. ; Gurung, Hem ; Alshabeeb Akil, Ammira S. ; Rose, Christopher M. ; Al-Maraghi, Aljazi ; Schubert, Alexander F. ; Newton, Kim ; French, Dorothy M. ; Bhat, Ajaz A. ; Soni, Naharmal ; Kschonsak, Marc ; Fakhro, Khalid A. ; Ndoja, Ada ; Webster, Joshua D. ; Dixit, Vishva M. ; Dugger, Debra L.

COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here, we link a homozygous DET1 R26W mutation to lethal developmental abnormalities in humans. Experimental cryo-electron microscopy of the DET1 complex with DDB1 and DDA1, as well as co-immunoprecipitation experiments, revealed that DET1 R26W impairs binding to DDB1, thereby compromising E3 ligase function. Accordingly, human-induced pluripotent stem cells homozygous for DET1 R26W expressed ETV4 and ETV5 highly, and exhibited defective mitochondrial homeostasis and aberrant caspase-dependent cell death when differentiated into neurons. Neuronal cell death was increased further in the presence of Det1 -deficient microglia as compared to WT microglia, indicating that the deleterious effects of the DET1 p.R26W mutation may stem from the dysregulation of multiple cell types. Mice lacking Det1 died during embryogenesis, while Det1 deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.

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