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Evolution of DNA replication origin specification and gene silencing mechanisms

Hu, Y. and Tareen, A. and Sheu, Y-J. and Ireland, W. T. and Speck, C. and Li, H. and Joshua-Tor, L. and Kinney, J. B. and Stillman, B. (2020) Evolution of DNA replication origin specification and gene silencing mechanisms. Nature Communications, 11 . Art. No. 5175. ISSN 2041-1723. PMCID PMC7560902.

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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.

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URLURL TypeDescription ItemCode CentralArticle Paper
Li, H.0000-0001-8085-8928
Joshua-Tor, L.0000-0001-8185-8049
Kinney, J. B.0000-0003-1897-3778
Stillman, B.0000-0002-9453-4091
Additional Information:© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received 02 July 2020; Accepted 22 September 2020; Published 14 October 2020. We thank Jennifer Shapp and Kevin Chen for help with experiments. This work was supported by NIH grants R01GM45436 and P01CA13106 to B.S. and R35GM133777 to J.B.K. L.J. is an Investigator of the Howard Hughes Medical Institute. This work was also supported by the Biotechnology and Biological Sciences Research Council (BB/S001387/1, BB/N000323/1) and by the Wellcome Trust (107903/Z/15/Z) to C.S. and NIH grant GM131754 to H.L. The Cold Spring Harbor Laboratory NextGen Sequencing Cancer Center Shared Resource is supported by grant P30 CA045508. Data availability: Unique biological reagents used in this study are available upon request to the corresponding author. Raw Illumina reads have been deposited to Sequence Read Archive (SRA) under accession PRJNA595459. Source data are provided with this paper. Code availability: Processed data files, analysis scripts, and scripts used for figure generation are available at Author Contributions: B.S., J.B.K., Y.H., Y-J.S., L.J., C.S., and H.L. designed the experiments, A.T., W.T.I., and J.B.K. developed the mutual information maximization algorithm. Y.H., J.B.K., and Y.-J.S. performed the experiments. Y.H., J.B.K., and B.S. wrote the paper. All authors analyzed aspects of the data. The authors declare no competing interests. Peer review information: Nature Communications thanks Anja-Katrin Bielinsky and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Biotechnology and Biological Sciences Research Council (BBSRC)BB/S001387/1
Biotechnology and Biological Sciences Research Council (BBSRC)BB/N000323/1
Wellcome Trust107903/Z/15/Z
NIHP30 CA045508
Subject Keywords:Molecular evolution; Origin selection
PubMed Central ID:PMC7560902
Record Number:CaltechAUTHORS:20200706-141604208
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Official Citation:Hu, Y., Tareen, A., Sheu, Y. et al. Evolution of DNA replication origin specification and gene silencing mechanisms. Nat Commun 11, 5175 (2020).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104229
Deposited By: Tony Diaz
Deposited On:06 Jul 2020 21:38
Last Modified:20 Oct 2020 17:46

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