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Structural insights into the function of ZRANB3 in replication stress response

Author

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  • Marek Sebesta

    (Sir William Dunn School of Pathology, University of Oxford)

  • Christopher D. O. Cooper

    (Sir William Dunn School of Pathology, University of Oxford
    Present address: Department of Biological Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK)

  • Antonio Ariza

    (Sir William Dunn School of Pathology, University of Oxford)

  • Christopher J. Carnie

    (Sir William Dunn School of Pathology, University of Oxford)

  • Dragana Ahel

    (Sir William Dunn School of Pathology, University of Oxford)

Abstract

Strategies to resolve replication blocks are critical for the maintenance of genome stability. Among the factors implicated in the replication stress response is the ATP-dependent endonuclease ZRANB3. Here, we present the structure of the ZRANB3 HNH (His-Asn-His) endonuclease domain and provide a detailed analysis of its activity. We further define PCNA as a key regulator of ZRANB3 function, which recruits ZRANB3 to stalled replication forks and stimulates its endonuclease activity. Finally, we present the co-crystal structures of PCNA with two specific motifs in ZRANB3: the PIP box and the APIM motif. Our data provide important structural insights into the PCNA-APIM interaction, and reveal unexpected similarities between the PIP box and the APIM motif. We propose that PCNA and ATP-dependency serve as a multi-layered regulatory mechanism that modulates ZRANB3 activity at replication forks. Importantly, our findings allow us to interpret the functional significance of cancer associated ZRANB3 mutations.

Suggested Citation

  • Marek Sebesta & Christopher D. O. Cooper & Antonio Ariza & Christopher J. Carnie & Dragana Ahel, 2017. "Structural insights into the function of ZRANB3 in replication stress response," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15847
    DOI: 10.1038/ncomms15847
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