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Nucleic Acids Research, 2003, Vol. 31, No. 9 2451-2459
© 2003 Oxford University Press

Stimulation of human DNA polymerase {epsilon} by MDM2

Hitomi Asahara, Ying Li, Jill Fuss, Dale S. Haines1, Nikolina Vlatkovic1, Mark T. Boyd1 and Stuart Linn*

Division of Biochemistry and Molecular Biology, Barker Hall, University of California, Berkeley, CA 94720-3202, USA and 1 MCP Hahnemann University Cancer Center, Philadelphia, PA 19102, USA

*To whom correspondence should be addressed. Tel: +1 510 642 7583; Fax: +1 510 643 3388; Email: slinn{at}socrates.berkeley.edu
Present addresses:
Ying Li, Pfizer, Inc., 4215 Sorrento Valley Boulevard, San Diego, CA 92121, USA
Jill Fuss, Lawrence Berkeley National Laboratory, MS 74–157, 1 Cyclotron Road, Berkeley, CA 94720, USA
Dale S. Haines, Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA
Nikolina Vlatkovic and Mark T. Boyd, Department of Surgery, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK

The human DNA polymerase {epsilon} catalytic subunit consists of a 140-kDa N-terminal domain that contains the catalytic activity and a 120-kDa C-terminal domain that binds to the other subunits and to exogenous peptides, including PCNA and MDM2. We report here that recombinant human MDM2 purified from insect cells or Escherichia coli stimulated the activity of DNA polymerase {epsilon} up to 10- and 40-fold, respectively, but not those of DNA polymerase ß or Klenow fragment of E.coli DNA polymerase I. Kinetic studies indicated that MDM2 increased the maximum velocity of the reaction, but did not change substrate affinities. The stimulation depended upon the interaction of the N-terminal 166 amino acid residues of MDM2 with the C-terminal domain of the full-length catalytic subunit, since the deletion of 166 amino acids from N-terminal of MDM2 or the removal of the C-terminal domain of DNA polymerase {epsilon} by trypsin digestion or competition for binding to it by the addition of excess C-terminal fragment eliminated the stimulation. Since DNA polymerase {epsilon} appears to be involved in DNA replication, recombination and repair synthesis, we suggest that MDM2 binding to DNA polymerase {epsilon} might be part of a reconfiguration process that allows DNA polymerase {epsilon} to associate with repair/recombination proteins in response to DNA damage.


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