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1 Laboratory of Genetics, University of Wisconsin Medical School, Madison, WI and
2 Molecular Biology Program, Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, NY
Requests for reprints: John H.J. Petrini, Memorial Sloan Kettering Cancer Center, RRL 901B, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-2927; Fax: (646) 422-2062. E-mail: petrinij{at}mskcc.org
The Mre11 complex undergoes dramatic relocalization in the nuclei of 
-irradiated and replicating human cells. In this study, we examined Mre11 complex localization and chromatin association in synchronous cultures to examine the molecular determinants of relocalization. The data indicate that the complex is deposited on chromatin in an S phase-specific manner. Mre11 complex chromatin association in S phase was resistant to detergent extraction, in contrast to that in -irradiated cells. The complex exhibits extensive colocalization with proliferating cell nuclear antigen throughout S phase, and chromatin loading is enhanced by replication fork stalling, suggesting that the replication fork is a site of Mre11 complex chromatin loading. This is supported by the observation that the complex localized to single-stranded DNA arising in hydroxyurea-treated cells. Although the Mre11 complex appears to function as a DNA damage sensor, limited colocalization with Brca1 or -H2AX was observed, arguing that neither DNA damage nor -H2AX is required for Mre11 complex chromatin loading. These data provide a potential molecular basis for promotion of sister chromatid association and recombination by the Mre11 complex as well as for ATM-Mre11 complex-dependent activation of cell cycle checkpoints.
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