The Many Roles of PCNA in Eukaryotic DNA Replication

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 post-translational 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.

Proliferating cell nuclear antigen restores the enzymatic activity of a DNA ligase I deficient in DNA binding

“…We constructed a double EhDNAligI‐Phe11Ala:Phe12Ala mutant aimed to eliminate the aromatic residues of the PIP box 3 10 α‐helix without completely eliminating its secondary structure 36, 37. We found that the enzymatic activity of EhDNAligI‐Phe11Ala:Phe12Ala mutant is simulated 9.8‐fold by wild‐type EhPCNA, supporting our previous results that the PIP box interaction is not necessary for nick‐sealing stimulation.…”

“…Because of the lack of stimulation of EhDNAlig by EhPCNA mutants, we were curious to test if EhDNAlig mutants that replace the most prominent hydrophobic interactions of the PIP box in EhDNAligI with EhPCNA would have an effect on nick-sealing activity upon incubation with wild-type and mutant forms of EhPCNA. We constructed a double EhDNAligI-Phe11Ala:Phe12Ala mutant aimed to eliminate the aromatic residues of the PIP box 3 10 a-helix without completely eliminating its secondary structure [36,37]. We found that the enzymatic activity of EhDNAligI-Phe11Ala:Phe12Ala mutant is simulated 9.8-fold by wild-type EhPCNA, supporting our previous results that the PIP box interaction is not necessary for nicksealing stimulation.…”

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

“…PCNA is a ring-shaped homotrimer that encircles the DNA (Figure 1), hence it is also referred to as a sliding clamp (Boehm et al, 2016a; Dieckman et al, 2012; Moldovan et al, 2007; Warbrick, 2000). PCNA has a highly conserved six-fold symmetry since each of the monomers are composed of two similarly folded globular regions united by a flexible interdomain connecting loop (IDCL).…”

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…This is a potentially attractive target due to its different expression profile in healthy proliferating cells vs. cancer cells. In healthy cells, PCNA appears to be expressed in the nucleus and is involved in DNA replication and repair (295), whereas in cancer cells, it is overexpressed on the cell surface (296). By constructing a monoclonal antibody against PCNA (14-25-9), the Porgador group was able to demonstrate that blocking this tumor antigen unleashes NK cell activity in-vitro and in-vivo, and promotes tumor clearance in murine xenograft models of autologous HNSCC patient NK cells (294).…”