Imperial College London
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ProfessorChristianSpeck

Faculty of Medicine, Institute of Clinical Sciences

Professor of Genome Biochemistry & Molecular Biology
 
 
 
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Contact

 

+44 (0)7961 815 557chris.speck Website CV

 
 
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Location

 

2.14BLMS BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@unpublished{Hu:2020:10.1038/s41467-020-18964-x,
author = {Hu, Y and Tareen, A and Sheu, Y-J and Ireland, WT and Speck, C and Li, H and Joshua-Tor, L and Kinney, JB and Stillman, B},
doi = {10.1038/s41467-020-18964-x},
publisher = {Cold Spring Harbor Laboratory},
title = {Evolution of DNA replication origin specification and gene silencing mechanisms},
url = {http://dx.doi.org/10.1038/s41467-020-18964-x},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - UNPB
AB  - DNA replication in eukaryotic cells initiates from chromosomal locations, called replication origins, that bind the Origin Recognition Complex (ORC) prior to S phase. Origin establishment is guided by well-defined DNA sequence motifs in Saccharomyces cerevisiae and some other budding yeasts, but most eukaryotes lack sequence-specific origins. At present, the mechanistic and evolutionary reasons for this difference are unclear. A 3.9 Å structure of S. cerevisiae ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) bound to origin DNA revealed, among other things, that a loop within Orc2 inserts into a DNA minor groove and an α-helix within Orc4 inserts into a DNA major groove1. We show that this Orc4 α-helix mediates the sequence-specificity of origins in S. cerevisiae. Specifically, mutations were identified within this α-helix that alter the sequence-dependent activity of individual origins as well as change global genomic origin firing patterns. This was accomplished using a massively parallel origin selection assay analyzed using a custom mutual-information-based modeling approach and a separate analysis of whole-genome replication profiling and statistics. Interestingly, the sequence specificity of DNA replication initiation, as mediated by the Orc4 α-helix, has evolved in close conjunction with the gain of ORC-Sir4-mediated gene silencing and the loss of RNA interference.
AU  - Hu,Y
AU  - Tareen,A
AU  - Sheu,Y-J
AU  - Ireland,WT
AU  - Speck,C
AU  - Li,H
AU  - Joshua-Tor,L
AU  - Kinney,JB
AU  - Stillman,B
DO  - 10.1038/s41467-020-18964-x
PB  - Cold Spring Harbor Laboratory
PY  - 2020///
TI  - Evolution of DNA replication origin specification and gene silencing mechanisms
UR  - http://dx.doi.org/10.1038/s41467-020-18964-x
UR  - https://www.biorxiv.org/content/10.1101/2020.07.04.187286v1
UR  - http://hdl.handle.net/10044/1/89371
ER  -
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