Cells vigorously protect the integrity of their genomes, because damage can lead to cancer or cell death. The genome – the complete set of a cell’s DNA – is most vulnerable as it replicates before a cell divides. Cancer cells are constantly dividing, so their genomes are constantly at risk.
Researchers at Washington University School of Medicine in St. Louis have identified a previously unknown signaling pathway that cells use to protect their DNA as it is copied. The results, which were published Jan. 24 in the journal Nature molecular cellThey suggest that targeting this pathway could potentially enhance the effectiveness of cancer therapies.
“A cell that cannot protect its genome will die,” said senior author Zhongsheng You, PhD, professor of cell biology and physiology. “This whole pathway that we found is there 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 potentially make such drugs more effective.” “
Transcriptional stress occurs when the cell’s DNA replication machinery encounters problems in copying the genome. Certain stretches of DNA are inherently difficult to transcribe, as they contain many repetitive sequences. Agents that damage DNA, such as radiation and toxic molecules, also cause transcriptional stress, as well as the activation of cancer-causing genes. Dozens of cancer drugs, including such widely used ones as cisplatin and doxorubicin, work by damaging DNA and increasing replication stress.
You study how cells protect their genomes as they replicate. Early in his career, he worked on the ATR-Chk1 genome-protecting pathway – a pathway that controls the cell division cycle and prevents the transcription machinery from completely shutting down and causing DNA breaks. Over the past eight years, he and his team have worked painstakingly to piece together another previously unknown genome-protecting pathway. With this new study, the final piece of the puzzle has fallen into place.
The process they discovered goes like this: When the DNA-replication machinery stops, a protein called Exo1 that usually follows the machine gets a little out of control. Exo1’s job is to perform quality control by snipping off incorrectly copied pieces of DNA, but when the machinery stops moving forward, Exo1 starts shearing randomly, cutting off pieces of DNA that then make their way from the nucleus to the fragment main part of the cell. DNA is not found outside the nucleus under normal conditions, so its presence in the main part of the cell sets off an alarm. Upon encountering a fragment of DNA, the sensor molecule triggers a chain of molecular events, including the release of a calcium ion from a cellular organelle known as the endoplasmic reticulum, which in turn shuts down Exo1, preventing it from shredding the genome any further. Until the machine problem can be fixed.
This most recent study describes the detection of DNA fragments as a warning signal that triggers a whole-genome protection response. The study was led by first author Shan Li, PhD, as a postdoctoral researcher and then team scientist in Yu’s lab. Li is now an assistant professor at Zhejiang University College of Medicine in Hangzhou, China. Co-author Lingzhen Kong, a graduate student, also made important contributions to the study.
Over the years, you and your colleagues have identified eight protein factors involved in this genome-protecting pathway. Most of them already have inhibitors in development that could be repurposed for cancer studies.
“Now that we have the pathway, we want to know if it can be targeted to treat cancer,” I said. “Lung, ovarian and breast cancer are intrinsically under replication stress. Other cancers are put under replication stress by chemotherapy drugs. This pathway protects cells from replication stress, so if we can 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, the process by which cells break down their unwanted materials.
“One of the most exciting things about this track is how it intersects with so many other tracks,” I said. “I’ve been focusing on cancer, but a lot of this can also apply to autoimmune diseases. Two of the proteins we identified have been linked to chronic activation of the immune response and autoimmune diseases. We want to understand the relationship between this proliferation-stress response pathway and the innate immune response pathway.” The work we’re doing is very fundamental, and it’s very exciting to connect the dots between these basic processes and see how they relate to human health and disease.”