Evolution of DNA replication origin specification and gene silencing mechanisms

Hu, Y, Tareen, A., Sheu, Y. J., Ireland, W. T., Speck, C., Li, H., Joshua-Tor, L., Kinney, J. B., Stillman, B. (October 2020) Evolution of DNA replication origin specification and gene silencing mechanisms. Nature Communications, 11 (1). p. 5175. ISSN 2041-1723

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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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA replication bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > yeast > Saccharomyces bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene silencing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > origin recognition complex bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > yeast
CSHL Authors:	Stillman, Bruce W. Kinney, Justin B. Joshua-Tor, Leemor Hu, Yi Tareen, Ammar Sheu, Yi-Jun
Communities:	CSHL labs > Joshua-Tor lab CSHL labs > Kinney lab CSHL labs > Stillman lab CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources > Next Generation Sequencing Service
Highlight:	Stillman, Bruce W.
Depositing User:	Matthew Dunn
Date:	14 October 2020
Date Deposited:	03 Dec 2020 19:21
Last Modified:	13 Feb 2024 21:22
PMCID:	PMC7560902
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39832

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