HOMOLOGOUS REGIONS OF FEN1 AND P21(CIP1) COMPETE FOR BINDING TO THE SAME SITE ON PCNA - A POTENTIAL MECHANISM TO COORDINATE DNA-REPLICATIONAND REPAIR

Following genomic damage, the cessation of DNA replication is co-ordin ated with onset of DNA repair; this co-ordination is essential to avoi d 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 all owing repair to continue, We have identified an interaction between PC NA 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 reg ion (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 pe ptide from p21(Cip1) competes with Fen1 peptides for binding to PCNA, disrupts the Fen1-PCNA complex in replicating cell extracts, and conco mitantly inhibits DNA synthesis, Competition between homologous region s of Fen1 and p21(Cip1) for binding to the same site on PCNA may provi de a mechanism to co-ordinate the functions of PCNA in DNA replication and repair.