Researchers at Washington University (WashU) School of Medicine report identifying a previously unknown signaling pathway in cells that protects their DNA as it is being copied – a discovery that suggests this pathway could be targeted for cancer treatment by interfere with the disease’s ability to duplicate its genome. The research was published today in the journal molecular cell.
“A cell that can’t protect its genome will die,” said senior author Zhongsheng You, PhD, a professor of cell biology and physiology at WashU. “This entire pathway that we found exists to protect the genome so that the cell can survive in the face of replication stress. By combining inhibitors of this pathway with chemotherapy drugs that target the DNA replication process, we can prevent such make medicines more effective.”
Your previous work focused on understanding how cells protect their genomes during replication. His early work involved investigating the ATR-Chk1 genome protection pathway, which controls the cell division cycle and prevents stalled replication machinery from completely failing and causing breaks in DNA. For the past eight years, his work has focused on completing the puzzle on another unknown genome protection pathway, the one now described in this new work.
A cell can undergo replication stress, causing its DNA replication activity to have problems copying the genome. This can be caused by a number of factors, including certain stretches of DNA that are difficult to duplicate due to a large number of repeated sequences, or things that damage the DNA itself, such as radiation and toxic molecules. Many commonly used cancer treatments work by damaging the DNA of cancer cells and increasing replication stress.
The new process discovered by the WashU researchers reveals that when the DNA duplication machinery in a cell stalls, the protein Exo1 that normally follows behind the machine to clean up miscopied bits of DNA reacts differently. Instead of precisely cutting out the miscopied pieces of DNA, Exo1 starts cutting haphazardly, splicing pieces of DNA that then come out of the nucleus and into the main part of the cell. Since DNA is not normally found outside the nucleus, a sensor molecule triggers a series of molecular events that ultimately prevent Exo1 from further cutting the DNA until the duplication machinery problem can be corrected.
The research detailed how their discovery of the DNA fragments is the warming signal of this genome protection response. During his years of research, You and colleagues have identified a total of eight proteins involved in this pathway, most of which already have inhibitors in development that could be reused as potential cancer targets.
“Now that we have the pathway, we want to know if it can be used to treat cancer,” you said. “Lung, ovarian and breast cancer are intrinsically under replication stress. Other cancers are put under replication stress by chemotherapy. This pathway protects cells from replication stress, so if we could block the pathway, it could improve patients’ response to cancer therapies.”
Many of the proteins in this pathway also play a role in other critical biological processes, including immunity, metabolism and autophagy, pointing to the potential to develop therapies for other diseases based on this new discovery.
“One of the most exciting things about this trail is how it crosses so many other trails,” you said. “I focused on cancer, but a lot of this could also apply to autoimmune diseases. Two of the proteins we identified have been associated with chronic activation of the immune response and autoimmune disease. We want to understand the relationship between this replication stress response pathway and the innate immune response pathway. The work we do is very basic, and it is so exciting to connect the dots between these fundamental processes and see how they relate to human health and disease.”