Human cells where DNA replication has been stopped. Image credit: Yang et al. (CC BY 4.0)
It takes a human cell between six and eight hours to copy all three billion letters of its genome. During this time, any interruption to the process can lead to genetic errors, putting the cell in danger of developing disease. To guard against this, cells use a checkpoint system, testing their own health before, during and after DNA replication to make sure that they are ready for the next step. If a cell detects a problem while copying its DNA, it responds by activating proteins called checkpoint kinases. These stop the cell from continuing until the problem is resolved. One of these checkpoint kinases is a protein called Chk1, which switches on if the cell gets stuck part way through copying its DNA.
To switch Chk1 on, the cell first needs to activate a protein called Claspin. Activating Claspin involves adding a chemical phosphate group to part of the Claspin protein. A third protein takes on this role, but its identity is controversial. Recent research points to a protein called casein kinase 1, but it was also possible that another protein, Cdc7 kinase, might be involved.
To find out, Yang et al. used gene editing to lower the levels of Cdc7 in human cancer cells. The cells were able to copy their DNA under normal conditions, but they struggled to activate Chk1 when DNA replication stopped. Biochemical tests revealed that this was because, without Cdc7, Claspin was not receiving the phosphate group it needed. Even so, the cancer cells still had some Chk1 activation, which meant that they must be able to activate some of their Claspin. So, Yang et al. tried getting rid of both Cdc7 and the other candidate protein, casein kinase 1. This stopped Chk1 activation completely, revealing that although the cancer cells mainly used Cdc7 to activate Claspin, they also used casein kinase 1. In tests on non-cancerous cells, the results were the other way around; healthy cells mainly used casein kinase 1 and relied less heavily on Cdc7.
These differences could prove useful for drug design. One of the challenges in cancer treatment is producing drugs that target cancer cells while leaving healthy cells unharmed. Future research could explore whether blocking Cdc7 could stop Chk1 activation in cancer cells only. This could stop the diseased cells fixing problems with their DNA replication, making it harder for them to survive.
