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Molecular and Cellular Biology, August 1999, p. 5373-5382, Vol. 19, No. 8
0270-7306/99/$04.00+0

A Novel Role in DNA Metabolism for the Binding of Fen1/Rad27 to PCNA and Implications for Genetic Risk

Ronald Gary,1,dagger Min S. Park,1 John P. Nolan,1 Helen L. Cornelius,1 Olga G. Kozyreva,2,Dagger Hiep T. Tran,2,§ Kirill S. Lobachev,2 Michael A. Resnick,2 and Dmitry A. Gordenin2,*

Life Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545,1 and Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 277092

Received 5 March 1999/Returned for modification 21 April 1999/Accepted 13 May 1999

Fen1/Rad27 nuclease activity, which is important in DNA metabolism, is stimulated by proliferating cell nuclear antigen (PCNA) in vitro. The in vivo role of the PCNA interaction was investigated in the yeast Rad27. A nuclease-defective rad27 mutation had a dominant-negative effect that was suppressed by a mutation in the PCNA binding site, thereby demonstrating the importance of the Rad27-PCNA interaction. The PCNA-binding defect alone had little effect on mutation, recombination, and the methyl methanesulfonate (MMS) response in repair-competent cells, but it greatly amplified the MMS sensitivity of a rad51 mutant. Furthermore, the PCNA binding mutation resulted in lethality when combined with a homozygous or even a heterozygous pol3-01 mutation in the 3'right-arrow5' exonuclease domain of DNA polymerase delta . These results suggest that phenotypically mild polymorphisms in DNA metabolic proteins can have dramatic consequences when combined.

* Corresponding author. Mailing address: National Institute of Environmental Health Sciences (NIEHS), Mail Drop D3-01, 101 TW Alexander Dr., P.O. Box 12233, Research Triangle Park, NC 27709. Phone: (919) 541-5190. Fax: (919) 541-7593. E-mail: gordenin{at}niehs.nih.gov.

dagger Present address: Department of Chemistry, University of Nevada, Las Vegas, NV 89154.

Dagger Present address: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3280.

§ Present address: LifeSensors, Inc., Malvern, PA 19355.

Molecular and Cellular Biology, August 1999, p. 5373-5382, Vol. 19, No. 8
0270-7306/99/$04.00+0


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