The fellowship of the rings: distinct pools of proliferating cell nuclear antigen trimer at work

The proliferating cell nuclear antigen (PCNA) is a homotrimeric ring-shaped protein that, by encircling DNA, may function as a sliding platform for proteins participating in various DNA transactions. PCNA plays a fundamental role in DNA replication and repair, but also in postreplicative events, like DNA methylation, chromatin assembly and remodeling, sister chromatid cohesion, and coordinates these activities with cell cycle control. However, relevant aspects of PCNA function are still not well understood, like the role of PCNA in the association with partner proteins, and how multiple protein interactions are orchestrated. Based on emerging evidence, I suggest that 1) PCNA interacting proteins may be reclassified in three major categories, namely, a) cell cycle control; b) DNA replication/repair; c) chromatin regulation/transcription. 2) PCNA is a negative regulator, rather than a processivity/recruitment factor, of chromatin-modifying enzymes. 3) At DNA replication sites, PCNA function may be envisaged with a model of "dynamic hand-off" of interacting partners that rapidly and transiently exchange in a mutually exclusive manner, while cyclin-dependent kinase (Cdk) 2 (CDK2) is stably bound to PCNA. The partner exchange might occur through a conformational change of the PCNA/protein/DNA complex allowing CDK2 to phosphorylate the partner protein, thereby enabling its hand-off from PCNA.