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, 5 (11), 1008-15

Radiation-mediated Proteolysis of CDT1 by CUL4-ROC1 and CSN Complexes Constitutes a New Checkpoint

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Radiation-mediated Proteolysis of CDT1 by CUL4-ROC1 and CSN Complexes Constitutes a New Checkpoint

Leigh Ann A Higa et al. Nat Cell Biol.

Erratum in

  • Nat Cell Biol. 2003 Dec;5(12):1122

Abstract

Genomic integrity is maintained by checkpoints that guard against undesired replication after DNA damage. Here, we show that CDT1, a licensing factor of the pre-replication complex (preRC), is rapidly proteolysed after UV- or gamma-irradiation. The preRC assembles on replication origins at the end of mitosis and during G1 to license DNA for replication in S phase. Once the origin recognition complex (ORC) binds to origins, CDC6 and CDT1 associate with ORC and promote loading of the MCM2-7 proteins onto chromatin, generating the preRC. We show that radiation-mediated CDT1 proteolysis is independent of ATM and CHK2 and can occur in G1-phase cells. Loss of the COP9-signalosome (CSN) or CUL4-ROC1 complexes completely suppresses CDT1 proteolysis. CDT1 is specifically polyubiquitinated by CUL4 complexes and the interaction between CDT1 and CUL4 is regulated in part by gamma-irradiation. Our study reveals an evolutionarily conserved and uncharacterized G1 checkpoint that induces CDT1 proteolysis by the CUL4-ROC1 ubiquitin E3 ligase and CSN complexes in response to DNA damage.

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