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Nucleic Acids Research, 2003, Vol. 31, No. 17 5202-5211
© 2003 Oxford University Press

Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA

Isabelle Salles-Passador1, Anil Munshi2, Dominique Cannella1, Vincent Pennaneach1,2, Stephane Koundrioukoff1, Michel Jaquinod1, Eric Forest1, Vladimir Podust3, Arun Fotedar2 and Rati Fotedar*,1

1 Institut de Biologie Structurale, J.-P. Ebel, 41 rue Jules Horowitz, F-38027 Grenoble Cedex 1, France, 2 Sidney Kimmel Cancer Center, 10835 Altman Road, San Diego, CA 92121, USA and 3 Department of Molecular Biology, Vanderbilt University, Nashville, TN 37235, USA

*To whom correspondence should be addressed. Tel: +33 4 38 78 96 15; Fax: +33 4 38 78 54 94; Email: fotedar{at}ibs.fr
Correspondence may also be addressed to Arun Fotedar. Tel: +1 858 450 5990; Fax: +1 858 450 3251; Email: afotedar{at}skcc.org
Present address:
Stephane Koundrioukoff, Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich Irchel, Zurich, Switzerland

Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. We have previously identified a distinct region, domain B, in the large subunit of human RF-C (RF-Cp145) which binds to PCNA. We show here that the functional interaction of RF-Cp145 with PCNA is regulated by cdk-cyclin kinases. Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA. A cdk-cyclin phosphorylation site, Thr506 in RF-Cp145, identified by mass spectrometry, is also phosphorylated in vivo. A Thr506->Ala RF-Cp145 domain B mutant is a poor in vitro substrate for cdk-cyclin kinase and, consequently, the ability of this mutant to bind PCNA was not suppressed by phosphorylation. By generating an antibody directed against phospho-Thr506 in RF-Cp145, we demonstrate that phosphorylation of endogenous RF-Cp145 at Thr506 is mediated by CDKs since it is abolished by treatment of cells with the cdk-cyclin inhibitor roscovitine. We have thus mapped an in vivo cdk-cyclin phosphorylation site within the PCNA binding domain of RF-Cp145.


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