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Review
. 2016:39:231-54.
doi: 10.1016/bs.enz.2016.03.003. Epub 2016 Apr 19.

The Many Roles of PCNA in Eukaryotic DNA Replication

E M Boehm  1 , M S Gildenberg  1 , M T Washington  2
Affiliations
Review

The Many Roles of PCNA in Eukaryotic DNA Replication

E M Boehm et al. Enzymes. 2016.

Abstract

Proliferating cell nuclear antigen (PCNA) plays critical roles in many aspects of DNA replication and replication-associated processes, including translesion synthesis, error-free damage bypass, break-induced replication, mismatch repair, and chromatin assembly. Since its discovery, our view of PCNA has evolved from a replication accessory factor to the hub protein in a large protein-protein interaction network that organizes and orchestrates many of the key events at the replication fork. We begin this review article with an overview of the structure and function of PCNA. We discuss the ways its many interacting partners bind and how these interactions are regulated by posttranslational modifications such as ubiquitylation and sumoylation. We then explore the many roles of PCNA in normal DNA replication and in replication-coupled DNA damage tolerance and repair processes. We conclude by considering how PCNA can interact physically with so many binding partners to carry out its numerous roles. We propose that there is a large, dynamic network of linked PCNA molecules at and around the replication fork. This network would serve to increase the local concentration of all the proteins necessary for DNA replication and replication-associated processes and to regulate their various activities.

Keywords: Break-induced replication; DNA polymerase; DNA repair; DNA replication; Mismatch repair; PCNA; Processivity factor; Proliferating cell nuclear antigen; Sliding clamp; Translesion synthesis.

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Figures

Figure 1
Figure 1. PCNA structure
(A) The structure of yeast PCNA (PBD: 1PLQ) [15] is shown from a front view and a side view. Domain 1 is blue, domain 2 is green, and the inter-domain connecting loop (IDCL) is red. (B) The structure of yeast PCNA bound to the PIP motif of the Cdc9 DNA ligase (PDB: 2OD8) [126] shown from a front view. The PIP motif is blue. Shown also are the sequences of several PIP motifs. (C) The structure of human PCNA bound to three full-length FEN1 proteins (PDB: 1UL1) [51] is shown from a front view. The three FEN1 molecules are blue, green, and red. (D) The structure of yeast SUMO-modified PCNA (PDB: 3PGE) [46] is shown from a front view. The SUMO moieties are blue.
Figure 2
Figure 2. The replication fork
A representation of the replication fork is shown with the leading strand on the bottom and the lagging strand on the top. PCNA is grey, pol ε is red, pol δ is orange, RPA is purple, and the CMG complex is green.
Figure 3
Figure 3. Separation-of-function mutations in PCNA
The locations of the separation-of-function mutations in yeast PCNA are shown from a front view. Mutations affecting translesion synthesis are blue, mutations affecting error-free damage bypass are red, mutations affecting break-induced replication are green, mutations affecting mismatch repair are yellow, and mutations affecting replication-coupled nucleosome assembly are orange.
Figure 4
Figure 4. Error-free damage bypass
A schematic of a stalled replication fork is shown. The leading strand is blue, the lagging strand is red, and the location of the DNA damage is indicated by a red square. The stalled replication fork is converted into the chicken foot intermediate, the chicken foot intermediate is extended, and the replication fork is then re-established.
Figure 5
Figure 5. Break-induced replication
A schematic of a replication fork with a nick in the leading strand template is shown. The leading strand is blue, and the lagging strand is red. This gives rise to a one-sided break. A schematic of a chicken foot intermediate is shown. Resolution of this four-way junction by cutting at the indicated sites also gives rise to a one-sided break. The one-sides break is converted into a D-loop, the D-loop is extended, and the replication fork is then re-established.
Figure 6
Figure 6. A replication factory
A representation of a single replication factory is shown containing two replication forks drawn to scale. Many PCNA molecules (grey) are shown on the DNA (black lines) as well as off the DNA. These PCNA molecules are linked together by many PCNA-interacting proteins (various colors) to form a large, flexible network surrounding the replication forks. The variously colored lines depict the intrinsically disordered regions of these PCNA-interacting proteins.
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