Abstract

DNA replication and repair are essential cellular processes that ensure genome duplication and safeguard the genome from deleterious mutations. Both processes utilize an abundance of enzymatic functions that need to be tightly regulated to ensure dynamic exchange of DNA replication and repair factors. Proliferating cell nuclear antigen (PCNA) is the major coordinator of faithful and processive replication and DNA repair at replication forks. Post-translational modifications of PCNA, ubiquitination and acetylation in particular, regulate the dynamics of PCNA-protein interactions. Proliferating cell nuclear antigen (PCNA) monoubiquitination elicits ‘polymerase switching’, whereby stalled replicative polymerase is replaced with a specialized polymerase, while PCNA acetylation may reduce the processivity of replicative polymerases to promote homologous recombination-dependent repair. While regulatory functions of PCNA ubiquitination and acetylation have been well established, the regulation of PCNA-binding proteins remains underexplored. Considering the vast number of PCNA-binding proteins, many of which have similar PCNA binding affinities, the question arises as to the regulation of the strength and sequence of their binding to PCNA. Here I provide an overview of post-translational modifications on both PCNA and PCNA-interacting proteins and discuss their relevance for the regulation of the dynamic processes of DNA replication and repair.

Highlights

  • DNA replication and repair are essential cellular processes that ensure genome duplication and safeguard the genome from deleterious mutations

  • I provide an overview of post-translational modifications on both Proliferating cell nuclear antigen (PCNA) and PCNA-interacting proteins and discuss their relevance for the regulation of the dynamic processes of DNA replication and repair

  • Given that translesion synthesis (TLS) polymerases can bind non-ubiquitinated PCNA via their PIP-box, albeit with lower affinity in vivo [45,51], and that PCNA is monoubiquitinated at lower levels in undamaged cells [52,60], it seems likely that TLS polymerases travel with the replicative polymerases

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Summary

Protein Interaction Interfaces on Proliferating Cell Nuclear Antigen

Each PCNA monomer contains two similar domains connected by the interdomain connector loop (IDCL). AlkB homologue 2 PCNA Interacting Motif (APIM) shares the binding interface, topology and common micromolar affinity with the PIP-box and is found in many DNA repair proteins [18,19]. Non-canonical PIP-boxes may lack Q1 (e.g., Pol η, κ, τ, poly (ADP-ribose) glycohydrolase (PARG), RNASEH2B) and/or one or both aromatic amino acids a7 /a8 (e.g., Pol τ, FANCM, the E3 ubiquitin-protein ligase TRAIP, the ATP-dependent DNA helicase Srs2) (Table 1 and Figure 4). This may result in a different mode of binding as in the case of Pol τ and Srs2 [20,21] (Figure 4D). Regulation of the strength and duration of interactions with PCNA can be only partially facilitated byTable differential binding affinities,ofwhich necessitates the binding existenceaffinities of additional levels of regulation

Sequence
Regulation
Post-Translational Modifications of Proliferating Cell Nuclear Antigen
Post-Translational Modifications of PCNA-Interacting Proteins
Perspective
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