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CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

Michael D Rainey1, Aisling Quinlan1, Chiara Cazzaniga1

  • 1Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.

EMBO Reports
|June 5, 2020
PubMed

Insights

CDC7 kinase coordinates MRE11-dependent DNA replication fork processes, including slowing, stabilization, and restart, independent of its origin firing role. This reveals CDC7

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • CDC7 kinase is crucial for DNA replication origin activation and the replication stress response.
  • MRE11 is involved in DNA double-strand break repair and replication fork stability.

Purpose of the Study:

  • To investigate the role of CDC7 kinase in MRE11-dependent processes at replication forks.
  • To elucidate CDC7's function beyond origin firing during replication stress.

Main Methods:

  • Utilized a specific chemical inhibitor of CDC7.
  • Employed a chemical genetic approach.
  • Observed protein localization and function at replication forks using microscopy and biochemical assays.

Main Results:

  • CDC7 activity is required for MRE11-dependent processes at replication forks, independent of origin firing.
  • CDC7 localizes to replication forks and mediates fork slowing alongside MRE11 upon topoisomerase inhibition.
  • CDC7 and MRE11 are retained on stalled forks, promoting processing and restart.
  • CDC7 inhibition leads to loss of MRE11 phosphorylation and localization.
  • CDC7 is essential for pathological MRE11 degradation at reversed forks in BRCA2-deficient cells.

Conclusions:

  • CDC7 is a key regulator of replication fork progression, processing, and integrity during replication interference.
  • CDC7 plays a dual role in DNA replication, influencing both initiation and elongation.
  • CDC7 represents a potential therapeutic target for anticancer strategies involving replication interference.
Keywords:
DNA replicationfork protectiongenome stabilitykinase inhibitor

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