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Cyclin binding Cy motifs have multiple activities in the initiation of DNA replication

View ORCID ProfileManzar Hossain, View ORCID ProfileKuhulika Bhalla, View ORCID ProfileBruce Stillman
doi: https://doi.org/10.1101/681668
Manzar Hossain
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Kuhulika Bhalla
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Bruce Stillman
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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  • For correspondence: stillman@cshl.edu
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Summary

The initiation of DNA replication involves the cell cycle-dependent assembly and disassembly of protein complexes, including the Origin Recognition Complex (ORC) and CDC6 AAA+ ATPases. We report that multiple short, linear protein motifs (SLiMs) within intrinsically disordered regions in ORC1 and CDC6, including Cyclin-binding (Cy) motifs, mediate Cyclin-CDK dependent and independent protein-protein interactions, conditional on cell cycle phase. The ORC1 Cy motif mediates an auto-regulatory self-interaction, and the same Cy motif prevents CDC6 binding to ORC1 in mitosis, but then facilitates the destruction of ORC1 in S phase. In contrast, in G1, the CDC6 Cy motif promotes ORC1-CDC6 interaction independent of Cyclin-CDK protein phosphorylation. CDC6 interaction with ORC also requires a basic region of ORC1 that in yeast mediates ORC-DNA interactions. We also demonstrate that protein phosphatase 1 binds directly to a SLiM in ORC1, causing de-phosphorylation upon mitotic exit. Thus, Cy-motifs have wider roles, functioning as a ligand and as a degron.

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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-NC 4.0 International license.
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Posted June 24, 2019.
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Cyclin binding Cy motifs have multiple activities in the initiation of DNA replication
Manzar Hossain, Kuhulika Bhalla, Bruce Stillman
bioRxiv 681668; doi: https://doi.org/10.1101/681668
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Cyclin binding Cy motifs have multiple activities in the initiation of DNA replication
Manzar Hossain, Kuhulika Bhalla, Bruce Stillman
bioRxiv 681668; doi: https://doi.org/10.1101/681668

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