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

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.