21 The Role of RF-C and PCNA Proteins in Maintaining Genomic Stability

Abstract

The eukaryotic replication clamp PCNA and its loader complex RF-C have been identified as essential components of the eukaryotic replication fork complex (Waga and Stillman 1998). When loaded at 3′ ends by RF-C, PCNA promotes efficient DNA synthesis and subsequently recruits factors required for Okazaki fragment maturation as described in Chapter 5. Since the same process is essential for synthesis during DNA repair, both PCNA and RF-C play vital roles in counteracting DNA damage. In addition, PCNA, which does not have prominent enzymatic activity, functions as a platform for various DNA metabolic enzymes, such as repair factors and proteins involved in DNA methylation and chromatin assembly. All of these proteins are crucial for the maintenance of replicated chromosome structures (Fig. 1) (Tsurimoto 1999; Maga and Hubscher 2003). Furthermore, PCNA is modified by ubiquitin and SUMO in response to DNA damage or during the cell cycle (Hoege et al. 2002), suggesting the presence of a molecular switch that directs PCNA to appropriate partners in damage-response pathways (Matunis 2002). Therefore, the importance of PCNA and RF-C in the precise transmission of genetic information in proliferating cells transcends their previously established roles as DNA elongation factors.

In yeast, several PCNA- and RF-C-related proteins have been implicated in checkpoint signaling, sister chromatid cohesion, and genome maintenance pathways (Ellison and Stillman 2003; Kim and MacNeill 2003; Majka and Burgers 2004). These proteins are highly conserved in eukaryotes and form PCNA-like heterotrimeric complexes or RF-C-like heteropentameric complexes. Because of their functional and structural similarities with PCNA...