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Updated: Sep 7, 2025

Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications
Published on: April 21, 2023
Post-Translational Modifications of PCNA: Guiding for the Best DNA Damage Tolerance Choice
Gemma Bellí1, Neus Colomina1, Laia Castells-Roca1
1Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, Universitat de Lleida, 25198 Lleida, Spain.
Abstract:
The sliding clamp PCNA is a multifunctional homotrimer mainly linked to DNA replication. During this process, cells must ensure an accurate and complete genome replication when constantly challenged by the presence of DNA lesions. Post-translational modifications of PCNA play a crucial role in channeling DNA damage tolerance (DDT) and repair mechanisms to bypass unrepaired lesions and promote optimal fork replication restart. PCNA ubiquitination processes trigger the following two main DDT sub-pathways: Rad6/Rad18-dependent PCNA monoubiquitination and Ubc13-Mms2/Rad5-mediated PCNA polyubiquitination, promoting error-prone translation synthesis (TLS) or error-free template switch (TS) pathways, respectively. However, the fork protection mechanism leading to TS during fork reversal is still poorly understood. In contrast, PCNA sumoylation impedes the homologous recombination (HR)-mediated salvage recombination (SR) repair pathway. Focusing on Saccharomyces cerevisiae budding yeast, we summarized PCNA related-DDT and repair mechanisms that coordinately sustain genome stability and cell survival. In addition, we compared PCNA sequences from various fungal pathogens, considering recent advances in structural features. Importantly, the identification of PCNA epitopes may lead to potential fungal targets for antifungal drug development.
Insights
Proliferating cell nuclear antigen (PCNA) modifications regulate DNA damage tolerance pathways. Understanding PCNA
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Proliferating cell nuclear antigen (PCNA) is a homotrimer crucial for DNA replication.
- Cells face constant DNA damage, necessitating accurate genome replication.
- Post-translational modifications of PCNA are key to DNA damage tolerance (DDT) and repair.
Purpose of the Study:
- To summarize PCNA-related DDT and repair mechanisms in *Saccharomyces cerevisiae*.
- To explore the role of PCNA modifications in maintaining genome stability and cell survival.
- To compare fungal PCNA sequences and identify potential antifungal drug targets.
Main Methods:
- Review of existing literature on PCNA function and modifications.
- Analysis of PCNA ubiquitination and sumoylation pathways.
- Comparative sequence analysis of PCNA from fungal pathogens.
Main Results:
- PCNA ubiquitination drives error-prone translesion synthesis (TLS) or error-free template switching (TS).
- PCNA sumoylation inhibits homologous recombination-mediated salvage recombination (SR).
- PCNA structural features and epitopes in fungal pathogens were identified.
Conclusions:
- PCNA modifications are critical for coordinating DNA repair and tolerance, ensuring genome stability.
- PCNA's role in fork protection during replication stress requires further investigation.
- Fungal PCNA epitopes represent potential targets for novel antifungal therapies.
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