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27.12.18 Cdc45 targets Rad53 to distinct replication complexes in budding yeast

last modified Jan 01, 2019 10:11 PM
In this Molecular Cell paper, the Zegerman lab present a single mechanism by which a checkpoint kinase targets replication initiation and elongation complexes, which may be relevant to human disease
27.12.18 Cdc45 targets Rad53 to distinct replication complexes in budding yeast

The Rad53 kinase is targeted to regulate replication initiation and stalled replisomes.

Helicase subunit Cdc45 targets the checkpoint kinase Rad53 to both replication initiation and elongation complexes after fork stalling

Can G et al. (2018) Molecular Cell 27 December (advance online publication).

DOI: 10.1016/j.molcel.2018.11.025

 

Highlights from the paper

  • Cdc45 targets Rad53 to inhibit replication initiation through Sld3
  • Rad53 binds to the replisome in part through Cdc45
  • A Meier-Gorlin mutation in Cdc45 prevents interaction with Rad53

 

Summary from the paper

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. 

 

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Read more about research in the Zegerman lab.

Watch Phil Zegerman describe his research on video.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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