EMBO Rep. 2020 Aug 5;21(8):e48920. doi: 10.15252/embr.201948920. | PubMed

Michael D Rainey¹, Aisling Quinlan¹, Chiara Cazzaniga¹, Sofija Mijic², Oliviano Martella¹, Jana Krietsch², Anja Göder¹, Massimo Lopes², Corrado Santocanale¹

1. Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
2. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.

Abstract

The CDC7 kinase is essential for the activation of DNA replication origins and has been implicated in the replication stress response. Using a highly specific chemical inhibitor and a chemical genetic approach, we now show that CDC7 activity is required to coordinate multiple MRE11-dependent processes occurring at replication forks, independently from its role in origin firing. CDC7 localizes at replication forks and, similarly to MRE11, mediates active slowing of fork progression upon mild topoisomerase inhibition. Both proteins are also retained on stalled forks, where they promote fork processing and restart. Moreover, MRE11 phosphorylation and localization at replication factories are progressively lost upon CDC7 inhibition. Finally, CDC7 activity at reversed forks is required for their pathological MRE11-dependent degradation in BRCA2-deficient cells. Thus, upon replication interference CDC7 is a key regulator of fork progression, processing and integrity. These results highlight a dual role for CDC7 in replication, modulating both initiation and elongation steps of DNA synthesis, and identify a key intervention point for anticancer therapies exploiting replication interference.

Presented By Aisling Quinlan | ORCID iD | https://santocanalelab.net/