Helicase Subunit Cdc45 Targets the Checkpoint Kinase Rad53 to Both Replication Initiation and Elongation Complexes after Fork Stalling.
View / Open Files
Publication Date
2019-02-07Journal Title
Mol Cell
ISSN
1097-2765
Publisher
Elsevier BV
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.. Mol 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 stabilization. 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 forkhead-associated (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
Cdc45, DNA damage, DNA replication, Rad53, budding yeast, checkpoint, replisome, Cell Cycle Proteins, Checkpoint Kinase 2, Congenital Microtia, DNA Damage, DNA Repair, DNA Replication, DNA, Fungal, DNA-Binding Proteins, Growth Disorders, Humans, Micrognathism, Mutation, Nuclear Proteins, Patella, Phosphorylation, Protein Binding, S Phase Cell Cycle Checkpoints, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Sponsorship
Worldwide Cancer Research (formerly AICR) (10-0908)
Cancer Research Uk (None)
Wellcome Trust (107056/Z/15/Z)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
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
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk