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Positive and negative control of helicase recruitment at a bacterial chromosome origin

Charles Winterhalter, Daniel Stevens, Stepan Fenyk, Simone Pelliciari, Elie Marchand, Nora B Cronin, Panos Soultanas, Tiago R. D. Costa, Aravindan Ilangovan, Heath Murray
doi: https://doi.org/10.1101/2021.08.16.456468
Charles Winterhalter
1Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK.
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Daniel Stevens
1Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK.
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Stepan Fenyk
1Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK.
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Simone Pelliciari
1Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK.
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Elie Marchand
2Research Unit in Biology of Microorganisms, Department of Biology, Université de Namur, Namur, Belgium.
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Nora B Cronin
3LonCEM, London Consortium for Cryo-EM, The Francis Crick Institute, London, NW1 1AT, UK.
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Panos Soultanas
4Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK.
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Tiago R. D. Costa
5Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College, London, SW7 2AZ, UK.
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Aravindan Ilangovan
6Blizard Institute, School of Biological and Behavioral Sciences, Queen Mary University of London, Newark street, London E1 2AT, UK.
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  • For correspondence: heath.murray@newcastle.ac.uk a.ilangovan@qmul.ac.uk
Heath Murray
1Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK.
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  • For correspondence: heath.murray@newcastle.ac.uk a.ilangovan@qmul.ac.uk
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ABSTRACT

The mechanisms responsible for helicase loading during the initiation of chromosome replication in bacteria are unclear. Here we report both a positive and a negative mechanism for directing helicase recruitment in the model organism Bacillus subtilis. Systematic mutagenesis of the essential replication initiation gene dnaD and characterization of DnaD variants revealed protein interfaces required for interacting with the master initiator DnaA and with a specific single-stranded DNA (ssDNA) sequence located in the chromosome origin (DnaD Recognition Element, “DRE”). We propose that the location of the DRE within the replication origin orchestrates recruitment of helicase to achieve bidirectional DNA replication. We also report that the developmentally expressed repressor of DNA replication initiation, SirA, acts by blocking the interaction of DnaD with DnaA, thereby inhibiting helicase recruitment to the origin. These findings significantly advance our mechanistic understanding of helicase recruitment and regulation during bacterial DNA replication initiation. Because DnaD is essential for the viability of clinically relevant Gram-positive pathogens, DnaD is an attractive target for drug development.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 16, 2021.
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Positive and negative control of helicase recruitment at a bacterial chromosome origin
Charles Winterhalter, Daniel Stevens, Stepan Fenyk, Simone Pelliciari, Elie Marchand, Nora B Cronin, Panos Soultanas, Tiago R. D. Costa, Aravindan Ilangovan, Heath Murray
bioRxiv 2021.08.16.456468; doi: https://doi.org/10.1101/2021.08.16.456468
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Positive and negative control of helicase recruitment at a bacterial chromosome origin
Charles Winterhalter, Daniel Stevens, Stepan Fenyk, Simone Pelliciari, Elie Marchand, Nora B Cronin, Panos Soultanas, Tiago R. D. Costa, Aravindan Ilangovan, Heath Murray
bioRxiv 2021.08.16.456468; doi: https://doi.org/10.1101/2021.08.16.456468

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