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Published May 15, 1997 | public
Journal Article

Homologous regions of Fen1 and p21^(Cip1) compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair

Abstract

Following genomic damage, the cessation of DNA replication is co-ordinated with onset of DNA repair; this co-ordination is essential to avoid mutation and genomic instability. To investigate these phenomena, we have analysed proteins that interact with PCNA, which is required for both DNA replication and repair. One such protein is p21^(Cip1), which inhibits DNA replication through its interaction with PCNA, while allowing repair to continue. We have identified an interaction between PCNA and the structure specific nuclease, Fen1, which is involved in DNA replication. Deletion analysis suggests that p21^(Cip1) and Fen1 bind to the same region of PCNA. Within Fen1 and its homologues a small region (10 amino acids) is sufficient for PCNA binding, which contains an 8 amino acid conserved PCNA-binding motif. This motif shares critical residues with the PCNA-binding region of p21^(Cip1). A PCNA binding peptide from p21^(Cip1) competes with Fen1 peptides for binding to PCNA, disrupts the Fen1-PCNA complex in replicating cell extracts, and concomitantly inhibits DNA synthesis. Competition between homologous regions of Fen1 and p21^(Cip1) for binding to the same site on PCNA may provide a mechanism to co-ordinate the functions of PCNA in DNA replication and repair.

Additional Information

© 1997 Stockton Press. Received 8 November 1996; revised 29 January 1997; accepted 29 January 1997. We would like to thank Fiona Cullen for assistance with DNA sequencing, Hiroyuki Ohkura and Peter Hall for helpful advice, Gus Reid for HPLC peptide purification, Angela Mehlert for mass spectrometry of the p21 nonapeptide, Fred Brewster for preparation of monoclonal antibodies, Jane Carter for assistance with densitometry, Byron Hann for critical reading of the manuscript, and Jo Murray for communicating results prior to publication. We are grateful to the Cancer Research Campaign for their generous support, and to the Royal Society of Edinburgh/ Caledonian Research Foundation for a personal research fellowship to LSC. DPL is a Gibb Fellow of the CRC and a Howard Hughes International Scholar.

Additional details

Created:
August 22, 2023
Modified:
October 20, 2023