PCNA (proliferating cell nuclear antigen, encoded by POL30) is a highly conserved homotrimeric ring-shaped complex that encircles DNA and functions as a sliding clamp and processivity factor for replicative DNA polymerases (3). PCNA is loaded by the replication factor C complex (RFC) onto primer-template sites of DNA and directs the replication machinery to the replication fork (4, 5). PCNA is also required for the establishment of sister chromatid cohesion (6), multiple forms of DNA repair, and various postreplication DNA processing reactions (7, 8), recruiting proteins involved in cell cycle control, nucleotide excision repair, mismatch repair and base excision repair (9, 10).

PCNA is subject to differential modification and functional targeting by both ubiquitin (Ubi4p) and SUMO (Smt3p), which channel PCNA to distinct functional pathways and regulate its roles in DNA replication and postreplication repair (8). PCNA has a single ubiquitination site (lysine 164), which is also the major SUMO acceptor site, although there is an additional, minor sumoylation site at lysine 127 (11, 12). PCNA is mono- and polyubiquitinated following DNA damage (13, 8), which is critical for cell survival as it facilitates the bypass of replication-blocking lesions (11, 12). Mono-ubiquitination of PCNA by Rad6p and Rad18p results in error-prone repair and involves the translesion synthesis polymerases eta (RAD30) and zeta (REV3, REV7), while polyubiquitination by Rad5p, Mms2p, and Ubc13p causes stalled replication forks to initiate error-free DNA repair (12, 8).

In contrast to ubiquitin, SUMO modification of PCNA is not induced by DNA damage (8). PCNA sumoylation on lysine 164 occurs in a Ubc9p-dependent manner in both normal and damaged cells during S phase, and functions to regulate normal DNA replication (8). SUMO modification of PCNA inhibits its ubiquitination and DNA repair functions (8), and recruits the helicase Hpr5p to prevent homologous recombination during S phase (11, 13, 14). Mutation of the ubiquitination and sumoylation sites in PCNA results in sensitivity to DNA damaging agents (7).

PCNA interacts with MSH (MutS Homolog), MLH (MutL Homolog), and ECO1 proteins both in S. cerevisiae and human (ESCO2), typically via their amino-terminal ends (5, 6, 15, 16, 17, 18, 19, 20). The prokaryotic homolog of PCNA is the beta-clamp processivity factor, and its interaction with E. coli polymerase IV is required for spontaneous and DNA damage-induced mutagenesis (21, 22).

Last updated: 2007-06-05