title: USP17- and SCFβTrCP--regulated degradation of DEC1 controls the DNA damage response.
abstract: In response to genotoxic stress, DNA damage checkpoints maintain the integrity of the genome by delaying cell cycle progression to allow for DNA repair. Here we show that the degradation of the basic helix-loop-helix (bHLH) transcription factor DEC1, a critical regulator of cell fate and circadian rhythms, controls the DNA damage response. During unperturbed cell cycles, DEC1 is a highly unstable protein that is targeted for proteasome-dependent degradation by the SCF(βTrCP) ubiquitin ligase in cooperation with CK1. Upon DNA damage, DEC1 is rapidly induced in an ATM/ATR-dependent manner. DEC1 induction results from protein stabilization via a mechanism that requires the USP17 ubiquitin protease. USP17 binds and deubiquitylates DEC1, markedly extending its half-life. Subsequently, during checkpoint recovery, DEC1 proteolysis is reestablished through βTrCP-dependent ubiquitylation. Expression of a degradation-resistant DEC1 mutant prevents checkpoint recovery by inhibiting the downregulation of p53. These results indicate that the regulated degradation of DEC1 is a key factor controlling the DNA damage response.
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sara
authors.initials: S
authors.lastname: D'Annibale
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roberto
authors.initials: R
authors.lastname: Magliozzi
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands The Netherlands Proteomics Center, Utrecht, The Netherlands.
authors.forename: Teck Yew
authors.initials: TY
authors.lastname: Low
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Jansen
authors.affiliation: Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Indra A
authors.initials: IA
authors.lastname: Shaltiel
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands The Netherlands Proteomics Center, Utrecht, The Netherlands.
authors.forename: Shabaz
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands The Netherlands Proteomics Center, Utrecht, The Netherlands.
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.affiliation: Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Rene H
authors.initials: RH
authors.lastname: Medema
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands d.guardavaccaro@hubrecht.eu.
authors.forename: Daniele
authors.initials: D
authors.lastname: Guardavaccaro
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D004249:DNA Damage; D015536:Down-Regulation; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
chemical_list: C403671:DELEC1 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D010450:Endopeptidases; C484854:USP17L2 protein, human; D046988:Proteasome Endopeptidase Complex