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. 2024 Jul;291(14):3147-3168.
doi: 10.1111/febs.17127. Epub 2024 Mar 31.

CDC7 inhibition drives an inflammatory response and a p53-dependent senescent-like state in breast epithelial cells

Chiara Cazzaniga  1 , Anja Göder  1 , Michael David Rainey  1 , Aisling Quinlan  1 , Simone Coughlan  2 , Stefanus Bernard  1   2 , Corrado Santocanale  1   2
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Free article

CDC7 inhibition drives an inflammatory response and a p53-dependent senescent-like state in breast epithelial cells

Chiara Cazzaniga et al. FEBS J. 2024 Jul.
Free article

Abstract

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.

Keywords: DNA replication; inflammation; kinase inhibitors; senescence.

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References

    1. González‐Garrido C & Prado F (2023) Novel insights into the roles of Cdc7 in response to replication stress. FEBS J 290, 3076–3088.
    1. Gillespie PJ & Blow JJ (2022) DDK: the outsourced kinase of chromosome maintenance. Biology (Basel) 11, 887.
    1. Rainey MD, Quinlan A, Cazzaniga C, Mijic S, Martella O, Krietsch J, Goder A, Lopes M & Santocanale C (2020) CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage. EMBO Rep 21, e48920.
    1. Kim JM, Kakusho N, Yamada M, Kanoh Y, Takemoto N & Masai H (2008) Cdc7 kinase mediates claspin phosphorylation in DNA replication checkpoint. Oncogene 27, 3475–3482.
    1. Rainey MD, Harhen B, Wang GN, Murphy PV & Santocanale C (2013) Cdc7‐dependent and ‐independent phosphorylation of claspin in the induction of the DNA replication checkpoint. Cell Cycle 12, 1560–1568.

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