(Ivanhoe Newswire) -- Cell cycle checkpoints act like molecular tripwires for damaged cells. Leave the tripwire in place for too long, however, and cancer cells will press on regardless, making them resistant to certain types of chemotherapy, according to researchers at the Salk Institute for Biological Studies.
"A lot of progress has been made in understanding the molecular details of checkpoint activation," senior author Tony Hunter, Ph.D., a professor in the Molecular and Cell Biology Laboratory was quoted as saying, "but checkpoint termination, which is essential for the resumption of cell cycle progression, is less well understood."
"If we could screen tumors for markers of chemo-resistance, we could then adjust the treatment accordingly," first author You-Wei Zhang, Ph.D., formerly a postdoctoral researcher in Hunter's lab and now an assistant professor at Case Western Reserve University in Cleveland, Ohio, was quoted as saying.
In response to DNA damage and blocked replication, eukaryotes activate the DNA damage checkpoint pathway, which stops the cell cycle, buying the cell time to repair damage and recover from stalled or collapsed replication forks. If not repaired, these errors can either kill a cell when it attempts to divide or lead to genomic instability and eventually to cancer.
A key role in this process is played by the checkpoint protein Chk1, which responds to stressful conditions induced by hypoxia, DNA damage–inducing cancer drugs, and irradiation. These same conditions set the protein up for eventual degradation. But how the cellular protein degradation machinery knows that it is time to dispose of activated Chk1 was unclear.
In his experiments, Zhang discovered that activation of Chk1 exposes a specific string of amino acids that attracts the attention of a protein known as Fbx6, short for F box protein 6. Fbx6 in turn brings in an enzyme complex that flags Chk1 proteins for degradation, allowing the cell to get rid of the activated checkpoint protein. Once Chk1 is eliminated, cells will resume the cell cycle progression, or, in the prolonged presence of replication stress, undergo programmed cell death. Yet some cancer cells keep dividing even in the presence of irreparable damage.
