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Molecular and Cellular Biology, September 2007, p. 6053-6067, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00532-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Mre11 Complex Mediates the S-Phase Checkpoint through an Interaction with Replication Protein A{triangledown} ,¶

Erin Olson,1,{dagger} Christian J. Nievera,1,{dagger} Enbo Liu,1,{ddagger} Alan Yueh-Luen Lee,1 Longchuan Chen,2 and Xiaohua Wu1*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,1 Department of Pathology, VA Medical Center, Long Beach, California 908222

Received 27 March 2007/ Returned for modification 14 May 2007/ Accepted 8 June 2007

The Mre11/Rad50/Nbs1 complex (MRN) plays an essential role in the S-phase checkpoint. Cells derived from patients with Nijmegen breakage syndrome and ataxia telangiectasia-like disorder undergo radioresistant DNA synthesis (RDS), failing to suppress DNA replication in response to ionizing radiation (IR). How MRN affects DNA replication to control the S-phase checkpoint, however, remains unclear. We demonstrate that MRN directly interacts with replication protein A (RPA) in unperturbed cells and that the interaction is regulated by cyclin-dependent kinases. We also show that this interaction is needed for MRN to correctly localize to replication centers. Abolishing the interaction of Mre11 with RPA leads to pronounced RDS without affecting phosphorylation of Nbs1 or SMC1 following IR. Moreover, MRN is recruited to sites at or adjacent to replication origins by RPA and acts there to inhibit new origin firing upon IR. These studies suggest a direct role of MRN at origin-proximal sites to control DNA replication initiation in response to DNA damage, thereby providing an important mechanism underlying the intra-S-phase checkpoint in mammalian cells.

* Corresponding author. Mailing address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037. Phone: (858) 784-7910. Fax: (858) 784-7978. E-mail: xiaohwu{at}scripps.edu

{triangledown} Published ahead of print on 25 June 2007.

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

{dagger} E.O. and C.J.N. contributed equally to this work.

{ddagger} Present address: Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA 92037.

Molecular and Cellular Biology, September 2007, p. 6053-6067, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00532-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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