Tudzarova, S;
Trotter, MWB;
Wollenschlager, A;
Mulvey, C;
Godovac-Zimmermann, J;
Williams, G;
Stoeber, K;
(2010)
Molecular Architecture of the DNA Replication Origin Activation Checkpoint.
EMBO Journal
, 29
(19)
3381 - 3394.
10.1038/emboj.2010.201.
![]() |
PDF
109201_emboj2010201a-1.pdf Available under License : See the attached licence file. Download (1MB) |
Abstract
Perturbation of DNA replication initiation arrests human cells in G1, pointing towards an origin activation checkpoint. We used RNAi against Cdc7 kinase to inhibit replication initiation and dissect this checkpoint in fibroblasts. We show that the checkpoint response is dependent on three axes coordinated through the transcription factor FoxO3a. In arrested cells, FoxO3a activates the ARF-|Hdm2-|p53 right arrow p21 pathway and mediates p15INK4B upregulation; p53 in turn activates expression of the Wnt/β-catenin signalling antagonist Dkk3, leading to Myc and cyclin D1 downregulation. The resulting loss of CDK activity inactivates the Rb-E2F pathway and overrides the G1-S transcriptional programme. Fibroblasts concomitantly depleted of Cdc7/FoxO3a, Cdc7/p15, Cdc7/p53 or Cdc7/Dkk3 can bypass the arrest and proceed into an abortive S phase followed by apoptosis. The lack of redundancy between the checkpoint axes and reliance on several tumour suppressor proteins commonly inactivated in human tumours provides a mechanistic basis for the cancer-cell-specific killing observed with emerging Cdc7 inhibitors.
Type: | Article |
---|---|
Title: | Molecular Architecture of the DNA Replication Origin Activation Checkpoint |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1038/emboj.2010.201 |
Publisher version: | http://dx.doi.org/10.1038/emboj.2010.201 |
Language: | English |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
URI: | https://discovery.ucl.ac.uk/id/eprint/109201 |
Archive Staff Only
![]() |
View Item |