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Molecular and Cellular Biology, May 2009, p. 2828-2840, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01830-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway{triangledown} ,{dagger}

Michalis Fragkos, Jaana Jurvansuu,{ddagger} and Peter Beard*

Ecole Polytechnique Federale de Lausanne, Faculty of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), 1015 Lausanne, Switzerland

Received 2 December 2008/ Returned for modification 15 January 2009/ Accepted 26 February 2009

Phosphorylation of H2AX ({gamma}H2AX) is an early sign of DNA damage induced by replication stalling. However, the role of H2AX in the repair of this type of DNA damage is still unclear. In this study, we used an inactivated adeno-associated virus (AAV) to induce a stalled replication fork signal and investigate the function of {gamma}H2AX. The cellular response to AAV provides a unique model to study {gamma}H2AX function, because the infection causes pannuclear H2AX phosphorylation without any signs of damage to the host genome. We found that pannuclear {gamma}H2AX formation is a result of ATR overactivation and diffusion but is independent of ATM. The inhibition of H2AX with RNA interference or the use of H2AX-deficient cells showed that {gamma}H2AX is dispensable for the formation and maintenance of DNA repair foci induced by stalled replication. However, in the absence of H2AX, the AAV-containing cells showed proteosome-dependent degradation of p21, followed by caspase-dependent mitotic catastrophe. In contrast, H2AX-proficient cells as well as H2AX-complemented H2AX–/– cells reacted by increasing p21 levels and arresting the cell cycle. The results establish a new role for H2AX in the p53/p21 pathway and indicate that H2AX is required for p21-induced cell cycle arrest after replication stalling.

* Corresponding author. Mailing address: EPFL, SV-ISREC, SV-1532, Station 19, 1015 Lausanne, Switzerland. Phone: 41-21-693 07 31. Fax: 41-21-693 07 20. E-mail: Peter.Beard{at}epfl.ch

{triangledown} Published ahead of print on 9 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Structural Biology and Biophysics, Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland.

Molecular and Cellular Biology, May 2009, p. 2828-2840, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01830-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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