TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress

Hoffmann, Saskia; Smedegaard, Stine; Nakamura, Kae; Mortuza, Gulnahar B.; Räschle, Markus; Opakua, Alain Ibáñez de; Oka, Yasuyoshi; Feng, Yunpeng; Blanco, Francisco J.; Mann, Matthias; Montoya, Guillermo; Groth, Anja; Bekker‐Jensen, Simon; Mailand, Niels

doi:10.1083/jcb.201506071

Cited by 69 publications

(90 citation statements)

References 39 publications

(45 reference statements)

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“…The result showed that the Pif1 peptide binds PCNA with a 19 μM K d and a stoichiometry of one Pif1 peptide per protomer of PCNA (Figure 1C). The affinity of this Pif1 epitope for PCNA is similar to that determined for the PIP motif of PCNA-binding factors such as TRAIP E3 ligase (31 μM K d ) (Hoffmann et al, 2016) and the P66 subunit of Pol δ (16 μM K d ) (Bruning and Shamoo, 2004). …”

Section: Resultssupporting

confidence: 70%

Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication

et al. 2017

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SUMMARY The S. cerevisiae Pif1 helicase functions with DNA polymerase (Pol) δ in DNA synthesis during break-induced replication (BIR), a conserved pathway responsible for replication fork repair and telomere recombination. Pif1 interacts with the DNA polymerase processivity clamp PCNA, but the functional significance of the Pif1-PCNA complex remains to be elucidated. Here, we solve the crystal structure of PCNA in complex with a non-canonical PCNA-interacting motif in Pif1. The structure guides the construction of a Pif1 mutant that is deficient in PCNA interaction. This mutation impairs the ability of Pif1 to enhance DNA strand displacement synthesis by Pol δ in vitro and also the efficiency of BIR in cells. These results provide insights into the role of the Pif1-PCNA-Pol δ ensemble during DNA break repair by homologous recombination.

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Section: Resultssupporting

confidence: 70%

Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication

et al. 2017

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“…[2,17] PIP-boxes positioned at the extreme protein Cterminus do not form a defined IDCLi nteraction, such as in TRAIP in which only two residues proceedt he PIP-box. [18] In comparison, neither the Nterminally located pol d p12 PIP-box nor the internally located pol i PIP-boxm ake extended contacts with the IDCL, even in peptides with sufficient length to do so. [19] The residues N-terminal tot he PIP-box also display av ariety of interactions acrossP CNA partners.…”

Section: Pcna-binding Partners Display Structural Variationmentioning

confidence: 97%

“…Both p21 and flap endonuclease 1 (FEN‐1) make extended β‐sheet contacts with the IDCL, with both PIP‐boxes located in the C terminus of the full‐length protein . PIP‐boxes positioned at the extreme protein C terminus do not form a defined IDCL interaction, such as in TRAIP in which only two residues proceed the PIP‐box . In comparison, neither the N‐terminally located pol δ p12 PIP‐box nor the internally located pol ι PIP‐box make extended contacts with the IDCL, even in peptides with sufficient length to do so .…”

Section: Pcna‐binding Partners Display Structural Variationmentioning

confidence: 99%

Targeting PCNA with Peptide Mimetics for Therapeutic Purposes

2019

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Proliferating cell nuclear antigen (PCNA) is an excellent inhibition target to shut down highly proliferative cells and thereby develop a broad‐spectrum cancer therapeutic. It interacts with a wide variety of proteins through a conserved motif referred to as the PCNA‐interacting protein (PIP) box. There is large sequence diversity between high‐affinity PCNA binding partners, but with conservation of the binding structure—a well‐defined 310‐helix. Herein, all current PIP‐box peptides crystallised with human PCNA are collated to reveal common trends between binding structure and affinity. Key intra‐ and intermolecular hydrogen‐bonding networks that stabilise the 310‐helix of PIP‐box partners are highlighted and related back to the canonical PIP‐box motif. High correlation with the canonical PIP‐box sequence does not directly afford high affinity. Instead, we summarise key interactions that stabilise the binding structure that leads to enhanced PCNA binding affinity. These interactions also implicate the “non‐conserved” residues within the PIP‐box that have previously been overlooked. Such insights will allow a more directed approach to develop therapeutic PCNA inhibitors.

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“…Such structures activate a stress response, mediated by checkpoint kinases, which helps stabilize and restart the forks thus preventing generation of DNA damage and genomic instability (Zeman and Cimprich, 2014). In addition to the ubiquitinated PCNA dependent ATM checkpoint described above, PCNA interacts with two ubiquitin ligases, TRAIP and HUWE1, and these interactions are required for efficient fork progression under replication stress conditions (Choe et al, 2016; Hoffmann et al, 2016). In both cases, PCNA was shown to not be a substrate for these ligases.…”

Section: Other Genome Stability Mechanismsmentioning

confidence: 99%

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

2017

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Proliferating Cell Nuclear Antigen (PCNA) lies at the center of the faithful duplication of eukaryotic genomes. With its distinctive doughnut-shaped molecular structure, PCNA was originally studied for its role in stimulating DNA polymerases. However, we now know that PCNA does much more than promote processive DNA synthesis. Because of the complexity of the events involved, cellular DNA replication poses major threats to genomic integrity. Whatever predicament lies ahead for the replication fork, PCNA is there to orchestrate the events necessary to handle it. Through its many protein interactions and various post-translational modifications, PCNA has far-reaching impacts on a myriad of cellular functions.

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TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress

Abstract: The E3 ubiquitin ligase TRAIP associates with replication forks through direct interaction with PCNA, promoting checkpoint signaling and genome stability after replication stress.

Cited by 69 publications

References 39 publications

Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication

Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication

Targeting PCNA with Peptide Mimetics for Therapeutic Purposes

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

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