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Published 16 August 2004. doi:10.1083/jcb.200312048
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 4, 455-463
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Dynamic targeting of the replication machinery to sites of DNA damage



David A. Solomon1, M. Cristina Cardoso2, and Erik S. Knudsen1

1 Department of Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267
2 Max Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany

Address correspondence to E.S. Knudsen, Dept. of Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267. Tel.: (513) 558-8885. Fax: (513) 558-4454. email: erik.knudsen{at}uc.edu; or D.A. Solomon, email: das67{at}georgetown.edu


Abstract

Components of the DNA replication machinery localize into discrete subnuclear foci after DNA damage, where they play requisite functions in repair processes. Here, we find that the replication factors proliferating cell nuclear antigen (PCNA) and RPAp34 dynamically exchange at these repair foci with discrete kinetics, and this behavior is distinct from kinetics during DNA replication. Posttranslational modification is hypothesized to target specific proteins for repair, and we find that accumulation and stability of PCNA at sites of damage requires monoubiquitination. Contrary to the popular notion that phosphorylation on the NH2 terminus of RPAp34 directs the protein for repair, we demonstrate that phosphorylation by DNA-dependent protein kinase enhances RPAp34 turnover at repair foci. Together, these findings support a dynamic exchange model in which multiple repair factors regulated by specific modifications have access to and rapidly turn over at sites of DNA damage.

Key Words: proliferating cell nuclear antigen; replication protein A; cisplatin; FRAP; foci

D.A. Solomon's present address is Dept. of Cell Biology, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20057.

Abbreviations used in this paper: APH, aphidicolin; CDDP, cisplatin or cis-diamminedichloroplatinum II; DNA-PK, DNA-dependent protein kinase; HU, hydroxyurea; PCNA, proliferating cell nuclear antigen.


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