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J. Biol. Chem., Vol. 280, Issue 13, 12927-12934, April 1, 2005

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DNA Lesion-specific Co-localization of the Mre11/Rad50/Nbs1 (MRN) Complex and Replication Protein A (RPA) to Repair Foci^*

Jacob G. Robison, Lu Lu, Kathleen Dixon¶, and John J. Bissler||

From the Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, Divison of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039

The DNA damage response, triggered by DNA replication stress or DNA damage, involves the activation of DNA repair and cell cycle regulatory proteins including the MRN (Mre11, Rad50, and Nbs1) complex and replication protein A (RPA). The induction of replication stress by hydroxyurea (HU) or DNA damage by camptothecin (CAMPT), etoposide (ETOP), or mitomycin C (MMC) led to the formation of nuclear foci containing phosphorylated Nbs1. HU and CAMPT treatment also led to the formation of RPA foci that co-localized with phospho-Nbs1 foci. After ETOP treatment, phospho-Nbs1 and RPA foci were detected but not within the same cell. MMC treatment resulted in phospho-Nbs1 foci formation in the absence of RPA foci. Consistent with the presence or absence of RPA foci, RPA hyperphosphorylation was present following HU, CAMPT, and ETOP treatment but absent following MMC treatment. The lack of co-localization of phospho-Nbs1 and RPA foci may be due to relatively shorter stretches of single-stranded DNA generated following ETOP and MMC treatment. These data suggest that, even though the MRN complex and RPA can interact, their interaction may be limited to responses to specific types of lesions, particularly those that have longer stretches of single-stranded DNA. In addition, the consistent formation of phospho-Nbs1 foci in all of the treatment groups suggests that the MRN complex may play a more universal role in the recognition and response to DNA lesions of all types, whereas the role of RPA may be limited to certain subsets of lesions.

Received for publication, December 21, 2004 , and in revised form, January 7, 2005.

^* This work was supported by National Institutes of Health Grants R01-NS34782 (to K. D.) and R01-DK061458 (to J. J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Present address: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.

^|| To whom correspondence should be addressed: Cincinnati Children's Hospital Medical Center, MLC 7022, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-4531; Fax: 513-636-7407; E-mail: john.bissler{at}cchmc.org.

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