Helicase Subunit Cdc45 Targets the Checkpoint Kinase Rad53 to Both Replication Initiation and Elongation Complexes after Fork Stalling.
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Can, G., Kauerhof, A. C., Macak, D., & Zegerman, P. (2019). Helicase Subunit Cdc45 Targets the Checkpoint Kinase Rad53 to Both Replication Initiation and Elongation Complexes after Fork Stalling.. Molecular cell, 73 (3), 562-573.e3. https://doi.org/10.1016/j.molcel.2018.11.025
Across eukaryotes, disruption of DNA replication causes an S-phase checkpoint response, which regulates multiple processes including inhibition of replication initiation and fork stabilisation. How these events are coordinated remains poorly understood. Here we show that the replicative helicase component Cdc45 targets the checkpoint kinase Rad53 to distinct replication complexes in the budding yeast Saccharomyces cerevisiae. Rad53 binds to FHA-interaction motifs in an unstructured loop region of Cdc45, which is phosphorylated by Rad53 itself, and this interaction is necessary for the inhibition of origin firing through Sld3. Cdc45 also recruits Rad53 to stalled replication forks, which we demonstrate is important for the response to replication stress. Finally we show that a Cdc45 mutation found in patients with Meier-Gorlin Syndrome disrupts the functional interaction with Rad53 in yeast. Together we present a single mechanism by which a checkpoint kinase targets replication initiation and elongation complexes, which may be relevant to human disease.
Patella, Humans, Saccharomyces cerevisiae, Micrognathism, DNA Damage, Growth Disorders, Cell Cycle Proteins, DNA-Binding Proteins, Saccharomyces cerevisiae Proteins, Nuclear Proteins, DNA, Fungal, DNA Repair, DNA Replication, Protein Binding, Phosphorylation, Mutation, S Phase Cell Cycle Checkpoints, Checkpoint Kinase 2, Congenital Microtia
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
WELLCOME TRUST (107056/Z/15/Z)
Cancer Research UK (A12700)
Worldwide Cancer Research (formerly AICR) (10-0908)
External DOI: https://doi.org/10.1016/j.molcel.2018.11.025
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287607
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/