UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Molecular Architecture of the DNA Replication Origin Activation Checkpoint

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. Green open access

[img] 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
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
Downloads since deposit
74Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item