RESUMEN

Drugs that block DNA replication prevent cell proliferation, which may result in anticancer activity. The latter is dependent on the drug's mode of action as well as on cell type-dependent responses to treatment. The inhibition of Cell division cycle 7-related protein kinase (CDC7), a key regulator of DNA replication, decreases the efficiency of origin firing and hampers the restarting of paused replication forks. Here, we show that upon prolonged CDC7 inhibition, breast-derived MCF10A cells progressively withdraw from the cell cycle and enter a reversible senescent-like state. This is characterised by the rewiring of the transcriptional programme with the induction of cytokine and chemokine expression and correlates with the accumulation of Cyclic GMP-AMP synthase (cGAS)-positive micronuclei. Importantly, cell fate depends on Cellular tumour antigen p53 (p53) function as cells no longer enter senescence but are funnelled into apoptosis upon p53 knockout. This work uncovers key features of the secondary response to CDC7 inhibitors, which could aid the development of these compounds as anticancer drugs.

Asunto(s)

Proteínas de Ciclo Celular , Senescencia Celular , Células Epiteliales , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Senescencia Celular/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Inflamación/patología , Inflamación/metabolismo , Inflamación/genética , Proliferación Celular/efectos de los fármacos , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico