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Regulation of PCNA–protein interactions for genome stability

Nature Reviews Molecular Cell Biology volume 14, pages 269–282 (2013)Cite this article

Subjects

Key Points

  • The sliding clamp proliferating cell nuclear antigen (PCNA) has a crucial role as a processivity factor for DNA replication in eukaryotic cells. PCNA provides a central platform for coordinating many replication-associated processes, such as DNA damage repair or bypass, chromatin establishment and sister chromatid cohesion.

  • A large number of cellular proteins compete for binding to a common surface on PCNA, necessitating tight, multilayered regulatory mechanisms that enable a fine-tuned interplay between PCNA and appropriate partner proteins at different stages of DNA replication and associated processes.

  • The PCNA-interacting protein (PIP) box, which is present in numerous proteins, is an important determinant for PCNA binding. Relative PCNA-binding affinities of PIP boxes establish a basic hierarchy of PCNA interactions.

  • Regulatory mechanisms controlling and modulating PCNA–protein interactions include post-translational modifications of PCNA and its associated proteins, accessory factors regulating PCNA–protein interactions and selective proteasome-dependent degradation of PCNA-bound proteins.

  • Mono- and polyubiquitylation of PCNA have key roles in enabling bypass of replication-associated DNA damage via translesion DNA synthesis and template switching, respectively.

  • Many new PCNA-binding proteins have been identified and characterized in recent years, broadening our understanding of the organization and regulation of PCNA-dependent processes underlying genome stability maintenance at the replication fork.

Abstract

Proliferating cell nuclear antigen (PCNA) has a central role in promoting faithful DNA replication, providing a molecular platform that facilitates the myriad protein–protein and protein–DNA interactions that occur at the replication fork. Numerous PCNA-associated proteins compete for binding to a common surface on PCNA; hence these interactions need to be tightly regulated and coordinated to ensure proper chromosome replication and integrity. Control of PCNA–protein interactions is multilayered and involves post-translational modifications, in particular ubiquitylation, accessory factors and regulated degradation of PCNA-associated proteins. This regulatory framework allows cells to maintain a fine-tuned balance between replication fidelity and processivity in response to DNA damage.

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Figure 1: PCNA as a master coordinator of replication fork-associated processes.
Figure 2: Structural features of PCNA–protein interactions.
Figure 3: PCNA ubiquitylation facilitates the recruitment of DNA damage bypass factors to enable replication past DNA lesions.
Figure 4: SUMOylation of PCNA promotes recruitment of anti-recombination factors to the replication fork.
Figure 5: PCNA–protein interactions can be controlled by post-translational modification of PCNA and associated proteins.

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Acknowledgements

The authors apologize to those whose important findings could not be cited owing to page limitations. They thank J. Lukas for critical reading of the manuscript. Work in the authors' laboratory is funded by grants from the Novo Nordisk Foundation, the Danish Medical Research Council, the Lundbeck Foundation and the Danish Cancer Society.

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  1. Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen N, 2200, Denmark

    Niels Mailand, Ian Gibbs-Seymour & Simon Bekker-Jensen

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  1. Niels Mailand
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  2. Ian Gibbs-Seymour
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DATABASES

Protein Data Bank

1AXC

1PLQ

2ZVK

3L10

3V60

FURTHER INFORMATION

Ubiquitin Signaling Group

Glossary

AAA+ ATPase

Superfamily of proteins that use ATP hydrolysis to remodel or translocate macromolecules in diverse cellular processes such as DNA replication, protein degradation, membrane fusion and signal transduction.

Isothermal titration calorimetry

(ITC). Gold standard biophysical technique to quantitatively determine the thermodynamic parameters of molecular interactions in solution.

Writers

Enzymes that can add chemical modifications to DNA or proteins.

Readers

Factors that bind proteins or DNA only when certain chemical modifications are present (or absent). Readers often recognize similar modifications through particular protein domains.

RAD6 epistasis group

Genes required for post-replication repair in Saccharomyces cerevisiae, including RAD6, RAD18, RAD5, methyl methanesulphonate sensitive 2 (MMS2) and ubiquitin-conjugating enzyme 13 (UBC13) (all of which are enzymes involved in protein ubiquitylation), as well as proliferating cell nuclear antigen (PCNA) and translesion DNA synthesis polymerases.

E2 ubiquitin-conjugating enzyme

A family of enzymes (comprising ∼40 members in mammalian cells) that, in conjunction with an E3 ubiquitin ligase, mediates the transfer of activated ubiquitin from the E2 active site Cys to a Lys residue in a target protein.

Cisplatin

A platinum-containing chemotherapeutic drug (cis-diamminedichloropltinum(II)) that induces DNA crosslinks (primarily intrastrand crosslinks and to a lesser extent interstrand crosslinks).

Erasers

Enzymes that can removechemical modifications from DNA or proteins.

UvrD-like domain

Domain found in a wide range of proteins that belong to the UvrD-like DNA helicase family, which are ATPases that unwind DNA with a 3′-5′ polarity.

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Mailand, N., Gibbs-Seymour, I. & Bekker-Jensen, S. Regulation of PCNA–protein interactions for genome stability. Nat Rev Mol Cell Biol 14, 269–282 (2013). https://doi.org/10.1038/nrm3562

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