Functional hierarchy of PCNA‐interacting motifs in DNA processing enzymes

• Published in: BioEssays Vol. 45; no. 6; pp. e2300020 - n/a
• Main Authors: Hamdan, Samir M., De Biasio, Alfredo
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2023
• Subjects: Chemical synthesis; cryo‐EM; Deoxyribonucleic acid; DNA; DNA - genetics; DNA biosynthesis; DNA ligases; DNA polymerase; DNA Polymerase III - chemistry; DNA Polymerase III - genetics; DNA Polymerase III - metabolism; DNA polymerases; DNA Replication; DNA-directed DNA polymerase; DNA-Directed DNA Polymerase - metabolism; Enzymes; Okazaki fragments maturation; Proliferating cell nuclear antigen; Proliferating Cell Nuclear Antigen - chemistry; Proliferating Cell Nuclear Antigen - genetics; Proliferating Cell Nuclear Antigen - metabolism; Protein Binding; Structure-function relationships; Substrates; proliferating cell nuclear antigen; DNA polymerases; Okazaki fragments maturation; DNA replication; DNA ligases; cryo-EM
• ISSN: 0265-9247; 1521-1878
• DOI: 10.1002/bies.202300020

Numerous eukaryotic DNA processing enzymes, such as DNA polymerases and ligases, bind the processivity factor PCNA, which acts as a platform to recruit and regulate the binding of enzymes to their DNA substrate. Multiple PCNA‐interacting motifs (PIPs) are present in these enzymes, but their individual structural and functional role has been a matter of debate. Recent cryo‐EM reconstructions of high‐fidelity DNA polymerase Pol δ (Pol δ), translesion synthesis DNA polymerase κ (Pol κ) and Ligase 1 (Lig1) bound to a DNA substrate and PCNA demonstrate that the critical interaction with PCNA involves the internal PIP proximal to the catalytic domain. The ancillary PIPs, located in long disordered regions, are instead invisible in the reconstructions, and appear to function as flexible tethers when the enzymes fall off the DNA. In this review, we discuss the recent structural advancements and propose a functional hierarchy for the PIPs in Pol δ, Pol κ, and Lig1. In this review, we analyze and compare the structural details of the interaction of PCNA with examplars of three types of enzymes: replicative DNA polymerases, translesion synthesis polymerases and DNA ligases, revealing functional differences in the multiple PCNA interacting motifs present in these enzymes.