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

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

Cell reports (2020-09-03)
Michael D Rainey, Declan Bennett, Rachel O'Dea, Melania E Zanchetta, Muriel Voisin, Cathal Seoighe, Corrado Santocanale
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.

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