Researchers have been examining the loss of control over the DNA replication and cell proliferation process since it was connected to the development of cancer. One of the most well-known and common traits of the disease in all types of cancer diagnoses is this this uncontrolled cellular replication and growth.
In healthy cells, this process is carefully regulated and controlled through pathways and cellular checkpoints. In a Nature Communications article published July 17, 2018, researchers identified a replication initiation determinant protein (RepID) that regulates replication through association of other proteins, drawing them directly to chromatin sites for replication initiation. One of these proteins is a Culling-RING E3 ubiquitin ligase (CRL) which one of many CRLs. CRL4 is recruited by RepID to chromatin in the very early stages of mitosis (cell cycle) prior to replication. CRL4 acts to degrade CDT1, a protein that promotes replication at the appropriate time in the cell cycle. Loss of CDT1 is the switch that tells a cell to only begin the DNA replication cycle once. In addition to CRLs, a complex called SCF is also part of the cell cycle progression in mammals. It, too, can facilitate degradation of chromatin proteins involved in regulation of mitosis and DNA replication later in the cell cycle (the S-phase).
In cases of RepID loss of expression or function, turning off that CDT1 switch is up to the SCF complex later in the cell cycle. However, because the degradation was originated after DNA replication began, the cell re-replicated its DNA because there were higher levels of CDT1 associated with the chromatin.
Part of the SCF complex is a protein called SKP2. This group of researchers treated the depleted RepID cancer cell cultures with a drug that inhibits SKP2, known as SZL-P1-41. Their findings indicated that cells expressing intact RepID were not affected by the SKP2 inhibitor but cells with no RepID showed high sensitivity to SKP2 inhibition. The RepID knockout cells entered apoptosis and there were no surviving colonies in cell culture. The researchers conclude that, “RepID expression levels might modulate the sensitivity of cancer cells to cullin-targeting drugs.”