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A new class of disordered elements controls DNA replication through initiator self-assembly

View ORCID ProfileMatthew W. Parker, Maren Bell, View ORCID ProfileMustafa Mir, Jonchee A. Kao, View ORCID ProfileXavier Darzacq, Michael R. Botchan, View ORCID ProfileJames M. Berger
doi: https://doi.org/10.1101/623058
Matthew W. Parker
1Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
2Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720, USA
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  • ORCID record for Matthew W. Parker
Maren Bell
2Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720, USA
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Mustafa Mir
2Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720, USA
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Jonchee A. Kao
2Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720, USA
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Xavier Darzacq
2Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720, USA
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Michael R. Botchan
2Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720, USA
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  • For correspondence: mbotchan@berkeley.edu jmberger@jhmi.edu
James M. Berger
1Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
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  • For correspondence: mbotchan@berkeley.edu jmberger@jhmi.edu
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SUMMARY

The initiation of DNA replication in metazoans occurs at thousands of chromosomal sites known as origins. At each origin, the Origin Recognition Complex (ORC), Cdc6, and Cdt1 co-assemble to load the Mcm2-7 replicative helicase onto chromatin. Current replication models envisage a linear arrangement of isolated origins functioning autonomously; the extent of inter-origin organization and communication is unknown. Here, we report that the replication initiation machinery of D. melanogaster unexpectedly undergoes liquid-liquid phase separation (LLPS) upon binding DNA in vitro. We find that ORC, Cdc6, and Cdt1 contain intrinsically disordered regions (IDRs) that drive LLPS and constitute a new class of phase separating elements. Initiator IDRs are shown to regulate multiple functions, including chromosome recruitment, initiator-specific co-assembly, and Mcm2-7 loading. These data help explain how CDK activity controls replication initiation and suggest that replication programs are subject to higher-order levels of inter-origin organization.

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Posted April 29, 2019.
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A new class of disordered elements controls DNA replication through initiator self-assembly
Matthew W. Parker, Maren Bell, Mustafa Mir, Jonchee A. Kao, Xavier Darzacq, Michael R. Botchan, James M. Berger
bioRxiv 623058; doi: https://doi.org/10.1101/623058
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A new class of disordered elements controls DNA replication through initiator self-assembly
Matthew W. Parker, Maren Bell, Mustafa Mir, Jonchee A. Kao, Xavier Darzacq, Michael R. Botchan, James M. Berger
bioRxiv 623058; doi: https://doi.org/10.1101/623058

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