[Frontiers in Bioscience 15, 840-853, June 1, 2010]

Mechanisms of ATR-mediated checkpoint signalling

Veronique A.J. Smits1, Daniel O. Warmerdam2, Yuse Martin 1, Raimundo Freire1

1Unidad de Investigacion, Hospital Universitario de Canarias, Tenerife, Spain, 2Department of Cell Biology and Genetics, Erasmus MC, Rotterdam, The Netherlands

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Essential function of ATR
4. Triggering ATR signalling
4.1. Lesions that activate the ATR pathway
4.2. The role of ATRIP and TopBP1
4.3. Rad17 and Rad9-Rad1-Hus1
4.4. Claspin and other mediators implicated in ATR signalling
5. ATR substrates and downstream responses
6. Spatio-temporal organisation
7. Recovery from checkpoint activation
7.1. Direct inactivation of Chk1
7.2. Plk1, Claspin and Wee1
8. Perspective
9. Acknowledgements
10. References

1. ABSTRACT

Cell cycle checkpoints maintain genomic integrity by delaying cell division in the presence of DNA damage or replication problems. A crucial player in this process is the ATR kinase. The rapid localisation of ATR to sites of genotoxic stress and the central role of this kinase in the checkpoint response lead to the suggestion that ATR functions as a sensor of DNA lesions. After activation, ATR phosphorylates and activates the effector kinase Chk1, thereby causing an inhibition in cell cycle progression. However, this would not be possible without the existence of many other proteins operating in this pathway. Here we review current progress in our understanding of the regulatory factors involved in the ATR-mediated checkpoint response, as well as resumption of cell cycle progression upon repair of the damage, thereby focussing on the mechanisms in mammalian cells.