DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks DOI Creative Commons
Anja Göder, Chrystelle Maric, Michael D. Rainey

и другие.

The Journal of Cell Biology, Год журнала: 2024, Номер 223(8)

Опубликована: Июнь 12, 2024

CDC7 kinase is crucial for DNA replication initiation and involved in fork processing stress response. Human requires the binding of either DBF4 or DRF1 its activity. However, it unclear whether two regulatory subunits target to a specific set substrates, thus having different biological functions, if they act redundantly. Using genome editing technology, we generated isogenic cell lines deficient DRF1: these cells are viable but present signs genomic instability, indicating that both can independently support bulk replication. Nonetheless, DBF4-deficient show altered efficiency, partial deficiency MCM helicase phosphorylation, alterations timing discrete regions. Notably, find function at forks entirely dependent on not DRF1. Thus, primary regulator activity, mediating most functions unperturbed upon interference.

Язык: Английский

CDC7 inhibition drives an inflammatory response and a p53‐dependent senescent‐like state in breast epithelial cells DOI Creative Commons
Chiara Cazzaniga, Anja Göder,

Michael David Rainey

и другие.

FEBS Journal, Год журнала: 2024, Номер 291(14), С. 3147 - 3168

Опубликована: Март 31, 2024

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 type-dependent responses to treatment. inhibition Cell division cycle 7-related protein kinase (CDC7), a key regulator replication, decreases efficiency origin firing and hampers restarting paused forks. Here, we show upon prolonged CDC7 inhibition, breast-derived MCF10A cells progressively withdraw from enter reversible senescent-like state. This characterised by rewiring transcriptional programme with induction cytokine chemokine expression correlates accumulation Cyclic GMP-AMP synthase (cGAS)-positive micronuclei. Importantly, fate depends Cellular tumour antigen p53 (p53) function no longer senescence but are funnelled into apoptosis knockout. work uncovers features secondary response inhibitors, could aid development these compounds drugs.

Язык: Английский

Процитировано

1
DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks DOI Creative Commons
Anja Göder, Chrystelle Maric, Michael D. Rainey

и другие.

The Journal of Cell Biology, Год журнала: 2024, Номер 223(8)

Опубликована: Июнь 12, 2024

CDC7 kinase is crucial for DNA replication initiation and involved in fork processing stress response. Human requires the binding of either DBF4 or DRF1 its activity. However, it unclear whether two regulatory subunits target to a specific set substrates, thus having different biological functions, if they act redundantly. Using genome editing technology, we generated isogenic cell lines deficient DRF1: these cells are viable but present signs genomic instability, indicating that both can independently support bulk replication. Nonetheless, DBF4-deficient show altered efficiency, partial deficiency MCM helicase phosphorylation, alterations timing discrete regions. Notably, find function at forks entirely dependent on not DRF1. Thus, primary regulator activity, mediating most functions unperturbed upon interference.

Язык: Английский

Процитировано

1