ATR Restrains DNA Synthesis and Mitotic Catastrophe in Response to CDC7 Inhibition

Cell Rep. 2020 Sep 1;32(9):108096. doi: 10.1016/j.celrep.2020.108096. | PubMed

Michael D Rainey¹, Declan Bennett², Rachel O'Dea¹, Melania E Zanchetta¹, Muriel Voisin¹, Cathal Seoighe², Corrado Santocanale³

1. Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway H91W2TY, Ireland.
2. School of Mathematics, Statistics, and Applied Mathematics, National University of Ireland Galway, Galway H91TK33, Ireland.
3. Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway H91W2TY, Ireland. Electronic address: corrado.santocanale@nuigalway.ie.

Abstract

DNA replication initiates from multiple origins, and selective CDC7 kinase inhibitors (CDC7is) restrain cell proliferation by limiting origin firing. We have performed a CRISPR-Cas9 genome-wide screen to identify genes that, when lost, promote the proliferation of cells treated with sub-efficacious doses of a CDC7i. We have found that the loss of function of ETAA1, an ATR activator, and RIF1 reduce the sensitivity to CDC7is by allowing DNA synthesis to occur more efficiently, notably during late S phase. We show that partial CDC7 inhibition induces ATR mainly through ETAA1, and that if ATR is subsequently inhibited, origin firing is unleashed in a CDK- and CDC7-dependent manner. Cells are then driven into a premature and highly defective mitosis, a phenotype that can be recapitulated by ETAA1 and TOPBP1 co-depletion. This work defines how ATR mediates the effects of CDC7 inhibition, establishing the framework to understand how the origin firing checkpoint functions.

Presented By Michael Rainey | ORCID iD | https://santocanalelab.net/