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Review
. 2023 Jun;45(6):e2300020.
doi: 10.1002/bies.202300020. Epub 2023 Apr 11.

Functional hierarchy of PCNA-interacting motifs in DNA processing enzymes

Samir M Hamdan  1 , Alfredo De Biasio  1
Affiliations
Review

Functional hierarchy of PCNA-interacting motifs in DNA processing enzymes

Samir M Hamdan et al. Bioessays. 2023 Jun.

Abstract

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.

Keywords: DNA ligases; DNA polymerases; DNA replication; Okazaki fragments maturation; cryo-EM; proliferating cell nuclear antigen.

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