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Structure of human Cdc45 and implications for CMG helicase function

Author

Listed:
  • Aline C. Simon

    (University of Cambridge)

  • Vincenzo Sannino

    (DNA Metabolism Laboratory, FIRC Institute of Molecular Oncology Foundation)

  • Vincenzo Costanzo

    (DNA Metabolism Laboratory, FIRC Institute of Molecular Oncology Foundation)

  • Luca Pellegrini

    (University of Cambridge)

Abstract

Cell division cycle protein 45 (Cdc45) is required for DNA synthesis during genome duplication, as a component of the Cdc45-MCM-GINS (CMG) helicase. Despite its essential biological function, its biochemical role in DNA replication has remained elusive. Here we report the 2.1-Å crystal structure of human Cdc45, which confirms its evolutionary link with the bacterial RecJ nuclease and reveals several unexpected features that underpin its function in eukaryotic DNA replication. These include a long-range interaction between N- and C-terminal DHH domains, blocking access to the DNA-binding groove of its RecJ-like fold, and a helical insertion in its N-terminal DHH domain, which appears poised for replisome interactions. In combination with available electron microscopy data, we validate by mutational analysis the mechanism of Cdc45 association with the MCM ring and GINS co-activator, critical for CMG assembly. These findings provide an indispensable molecular basis to rationalize the essential role of Cdc45 in genomic duplication.

Suggested Citation

  • Aline C. Simon & Vincenzo Sannino & Vincenzo Costanzo & Luca Pellegrini, 2016. "Structure of human Cdc45 and implications for CMG helicase function," Nature Communications, Nature, vol. 7(1), pages 1-15, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11638
    DOI: 10.1038/ncomms11638
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    Cited by:

    1. Aina Maria Mas & Enrique Goñi & Igor Ruiz de los Mozos & Aida Arcas & Luisa Statello & Jovanna González & Lorea Blázquez & Wei Ting Chelsea Lee & Dipika Gupta & Álvaro Sejas & Shoko Hoshina & Alexandr, 2023. "ORC1 binds to cis-transcribed RNAs for efficient activation of replication origins," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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