Cells diligently protect the integrity of their genomes, as damage can lead to cancer or cell death. The genome — a cell’s complete set of DNA — is most vulnerable as it duplicates 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 findings, published Jan. 24 in the journal molecular cellsuggest that targeting this pathway could potentially increase the potency of cancer therapies.
“A cell that can’t protect its genome will die,” said senior author Zhongsheng You, PhD, a professor of cell biology and physiology. “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.”
Replication stress occurs when the cell’s DNA duplication machinery encounters problems copying the genome. Certain stretches of DNA are inherently difficult to copy because they contain many repeated sequences. Factors that damage DNA, such as radiation and toxic molecules, also cause replication stress, as well as the activation of cancer-causing genes. Dozens of anticancer drugs, including commonly used drugs such as cisplatin and doxorubicin, work by damaging DNA and increasing replication stress.
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You study how cells protect their genomes while they are being duplicated. Early in his career, he worked on the ATR-Chk1 genome protection pathway – a pathway that controls the cell division cycle and prevents stalled replication machinery from completely failing and causing breaks in DNA. For the past eight years, he and his team have painstakingly pieced together another previously unknown genome protection pathway. With this new study, the last piece of the puzzle falls into place.
The process they discovered goes like this: When the DNA duplication machine jams, a protein called Exo1 that normally follows behind the machine gets a little out of control. Exo1’s job is to perform quality control by excising miscopied bits of DNA, but when the machine stops moving forward, Exo1 begins to haphazardly excise and cleave off bits of DNA that are then removed from the nucleus and into most of it. off the body. the cell. DNA is not found outside the nucleus under normal circumstances, so its presence in most of the cell raises alarm. Upon encountering a DNA fragment, a sensor molecule triggers a cascade of molecular events, including the release of the calcium ion from a cellular organelle known as the endoplasmic reticulum, which in turn disables Exo1, preventing it from further entering the genome. until the problem with the machine can be solved.
This latest study describes the discovery of DNA fragments as the warning signal that triggers the entire genome protection response. The study was led by first author Shan Li, PhD, as a postdoctoral researcher and then as a staff scientist in You’s lab. Li is now an assistant professor at Zhejiang University School of Medicine in Hangzhou, China. Co-author Lingzhen Kong, a graduate student, also made significant contributions to the study.
Over the years, you and colleagues have identified eight protein factors involved in this genome protection pathway. Most of them already have inhibitors in development that can be reused for cancer studies.
“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.”
Several 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 own unwanted materials.
“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.”
Reference: Li S, Kong L, Meng Y, et al. Cytosolic DNA sensing by cGAS/STING promotes TRPV2-mediated Ca2+ release to protect stressed replication forks. Mole cell. 2023. doi: 10.1016/j.molcel.2022.12.034
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