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

Abstract

Proliferating Cell Nuclear Antigen (PCNA) lies at the center of the faithful duplication of eukaryotic genomes. With its distinctive doughnut-shaped molecular structure, PCNA was originally studied for its role in stimulating DNA polymerases. However, we now know that PCNA does much more than promote processive DNA synthesis. Because of the complexity of the events involved, cellular DNA replication poses major threats to genomic integrity. Whatever predicament lies ahead for the replication fork, PCNA is there to orchestrate the events necessary to handle it. Through its many protein interactions and various post-translational modifications, PCNA has far-reaching impacts on a myriad of cellular functions.

Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication

“…The conserved PIP-box sequence Q 1 x 2 x 3 h 4 x 5 x 6 a 7 a 8 harbors an invariable glutamine residue at position 1, wherein “x” is any amino acid, “h” is moderately hydrophobic (L/I/M), and “a” is highly hydrophobic (F/Y) (Choe and Moldovan, 2017; Mailand et al, 2013). The PCNA-binding epitope of Pif1 G 1 I 2 A 3 A 4 M 5 L 6 Q 7 R 8 lacks the conserved Q residue, which normally associates with the “Q pocket” of PCNA to orient PIP-box residues h 4 , a 7 , and a 8 for interaction with the PCNA hydrophobic pocket.…”

“…PCNA is a ring-shaped homotrimer that associates with various DNA polymerases and enhances the processivity of the replicative Pol δ and Pol ε (Burgers and Gerik, 1998; Johansson et al, 2004; Li et al, 2009). In addition, PCNA associates with and regulates the activities of other protein factors in DNA replication, DNA damage repair and bypass, chromatin remodeling, and cell cycle control (Choe and Moldovan, 2017). …”

Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism

“…4a) play key roles in TLS regulation (13, 145). Furthermore, post-translational modifications of PCNA and polymerases have been shown to influence cell cycle, replication fork movement, polymerase switch, and TLS activities (146, 147). Rev1 serves as a TLS hub and binds both TLS insertion polymerase (η, ι or κ) via RIR (Rev1 interacting region) (Fig.…”

Simultaneous dual-channel imaging to quantify interdependent protein recruitment to laser-induced DNA damage sites

“…PARP1 synthesizes poly(ADP-ribose) (PAR) from NAD, while PARG removes PAR by cleaving glycosidic bonds between ADP-ribose units [13]. PCNA is a ring-shaped clamp around DNA that serves as a loading platform for proteins involved in DNA replication and repair [14]. ALC1 is an SNF2-type chromatin remodeling ATPase, which is activated upon PAR binding to its macro domain at DNA damage sites [15,16].…”

“…PCNA remains stably bound at DNA damage sites to coordinate timely recruitment of DNA replication and repair factors [6,33,34]. As a ring-shaped homotrimer, PCNA encircles and slides along DNA, and recruits proteins via the interdomain connector loop on the outer surface serving as the common PCNA-protein interaction interface [14]. Structure-specific endonuclease ZRANB3, exonuclease EXO1, DNA methyl transferase DNMT1, replication licensing factor CDT1, PCNA loader RFC1 and PARG bind PCNA via the PCNA-interacting protein motif (PIP-box), which also mediates their recruitment to laser-induced DNA damage sites in a PCNA-dependent fashion [35–42].…”