USP17- and SCFβTrCP-regulated degradation of DEC1 controls the DNA damage response

Jihoon Kim, Sara D'Annibale, Roberto Magliozzi, Low Teck Yew, Petra Jansen, Indra A. Shaltiel, Shabaz Mohammed, Albert J R Heck, Rene H. Medema, Daniele Guardavaccaro

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 SCFβTrCP 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.

Original languageEnglish
Pages (from-to)4177-4185
Number of pages9
JournalMolecular and Cellular Biology
Volume34
Issue number22
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

Fingerprint

DNA Damage
Ubiquitin
Cell Cycle
Basic Helix-Loop-Helix Transcription Factors
Ubiquitination
Proteasome Endopeptidase Complex
Ligases
Circadian Rhythm
DNA Repair
Proteolysis
Half-Life
Proteins
Peptide Hydrolases
Down-Regulation
Genome

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Kim, J., D'Annibale, S., Magliozzi, R., Teck Yew, L., Jansen, P., Shaltiel, I. A., ... Guardavaccaro, D. (2014). USP17- and SCFβTrCP-regulated degradation of DEC1 controls the DNA damage response. Molecular and Cellular Biology, 34(22), 4177-4185. https://doi.org/10.1128/MCB.00530-14

USP17- and SCFβTrCP-regulated degradation of DEC1 controls the DNA damage response. / Kim, Jihoon; D'Annibale, Sara; Magliozzi, Roberto; Teck Yew, Low; Jansen, Petra; Shaltiel, Indra A.; Mohammed, Shabaz; Heck, Albert J R; Medema, Rene H.; Guardavaccaro, Daniele.

In: Molecular and Cellular Biology, Vol. 34, No. 22, 01.01.2014, p. 4177-4185.

Research output: Contribution to journalArticle

Kim, J, D'Annibale, S, Magliozzi, R, Teck Yew, L, Jansen, P, Shaltiel, IA, Mohammed, S, Heck, AJR, Medema, RH & Guardavaccaro, D 2014, 'USP17- and SCFβTrCP-regulated degradation of DEC1 controls the DNA damage response', Molecular and Cellular Biology, vol. 34, no. 22, pp. 4177-4185. https://doi.org/10.1128/MCB.00530-14
Kim, Jihoon ; D'Annibale, Sara ; Magliozzi, Roberto ; Teck Yew, Low ; Jansen, Petra ; Shaltiel, Indra A. ; Mohammed, Shabaz ; Heck, Albert J R ; Medema, Rene H. ; Guardavaccaro, Daniele. / USP17- and SCFβTrCP-regulated degradation of DEC1 controls the DNA damage response. In: Molecular and Cellular Biology. 2014 ; Vol. 34, No. 22. pp. 4177-4185.
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