DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks.

CDC7 kinase is crucial for DNA replication initiation and is involved in fork processing and replication stress response. Human CDC7 requires the binding of either DBF4 or DRF1 for its activity. However, it is unclear whether the two regulatory subunits target CDC7 to a specific set of substrates, thus having different biological functions, or if they act redundantly.

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

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.

PTBP1 enforces ATR-CHK1 signaling determining the potency of CDC7 inhibitors.

CDC7 kinase is crucial for DNA replication initiation and fork processing. CDC7 inhibition mildly activates the ATR pathway, which further limits origin firing; however, to date the relationship between CDC7 and ATR remains controversial. We show that CDC7 and ATR inhibitors are either synergistic or antagonistic depending on the degree of inhibition of each individual kinase.

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

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.

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage.

The CDC7 kinase is essential for the activation of DNA replication origins and has been implicated in the replication stress response. Using a highly specific chemical inhibitor and a chemical genetic approach, we now show that CDC7 activity is required to coordinate multiple MRE11-dependent processes occurring at replication forks, independently from its role in origin firing. CDC7 localizes at replication forks and, similarly to MRE11, mediates active slowing of fork progression upon mild topoisomerase inhibition.