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Mol Cell Biol. 2014 Nov 15;34(22):4177-85. doi: 10.1128/MCB.00530-14. Epub 2014 Sep 8.

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

Author information

1
Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
2
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.
3
Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
4
Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands d.guardavaccaro@hubrecht.eu.

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.

PMID:
25202122
PMCID:
PMC4248718
DOI:
10.1128/MCB.00530-14
[Indexed for MEDLINE]
Free PMC Article

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