Helicase Subunit Cdc45 Targets the Checkpoint Kinase Rad53 to Both Replication Initiation and Elongation Complexes after Fork Stalling.
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Publication Date
2019-02Journal Title
Molecular cell
ISSN
1097-2765
Publisher
Elsevier
Volume
73
Issue
3
Pages
562-573.e3
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
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
Abstract
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.
Keywords
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
Sponsorship
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)
Identifiers
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