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Evolution of DNA replication origin specification and gene silencing mechanisms

Author

Listed:
  • Y. Hu

    (Cold Spring Harbor Laboratory
    Stony Brook University)

  • A. Tareen

    (Cold Spring Harbor Laboratory
    Cold Spring Harbor Laboratory)

  • Y-J. Sheu

    (Cold Spring Harbor Laboratory)

  • W. T. Ireland

    (California Institute of Technology)

  • C. Speck

    (Imperial College London)

  • H. Li

    (Van Andel Institute)

  • L. Joshua-Tor

    (Cold Spring Harbor Laboratory
    Howard Hughes Medical Institute)

  • J. B. Kinney

    (Cold Spring Harbor Laboratory
    Cold Spring Harbor Laboratory)

  • B. Stillman

    (Cold Spring Harbor Laboratory)

Abstract

DNA replication in eukaryotic cells initiates from replication origins that bind the Origin Recognition Complex (ORC). Origin establishment requires well-defined DNA sequence motifs in Saccharomyces cerevisiae and some other budding yeasts, but most eukaryotes lack sequence-specific origins. A 3.9 Å structure of S. cerevisiae ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) bound to origin DNA revealed that a loop within Orc2 inserts into a DNA minor groove and an α-helix within Orc4 inserts into a DNA major groove. Using a massively parallel origin selection assay coupled with a custom mutual-information-based modeling approach, and a separate analysis of whole-genome replication profiling, here we show that the Orc4 α-helix contributes to the DNA sequence-specificity of origins in S. cerevisiae and Orc4 α-helix mutations change genome-wide origin firing patterns. The DNA sequence specificity of replication origins, mediated by the Orc4 α-helix, has co-evolved with the gain of ORC-Sir4-mediated gene silencing and the loss of RNA interference.

Suggested Citation

  • Y. Hu & A. Tareen & Y-J. Sheu & W. T. Ireland & C. Speck & H. Li & L. Joshua-Tor & J. B. Kinney & B. Stillman, 2020. "Evolution of DNA replication origin specification and gene silencing mechanisms," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18964-x
    DOI: 10.1038/s41467-020-18964-x
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