Evolution of DNA replication origin specification and gene silencing mechanisms

Y. Hu, A. Tareen, Y-J. Sheu, W. T. Ireland, C. Speck, H. Li, L. Joshua-Tor, J. B. Kinney and B. Stillman ()
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Y. Hu: Cold Spring Harbor Laboratory
A. Tareen: 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
J. B. Kinney: Cold Spring Harbor Laboratory
B. Stillman: Cold Spring Harbor Laboratory

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18964-x

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