Targeting Newly Identified Pathways May Boost Potency of Anticancer Drugs – Washington University School of Medicine, St. Louis

Cells eagerly protect their genomic integrity, as damage can lead to cancer and cell death. The genome, a cell’s complete set of DNA, is most vulnerable while it is being replicated before the cell divides. Because cancer cells are constantly dividing, their genomes are at constant risk.

Researchers at the Washington University School of Medicine in St. Louis have identified a previously unknown signaling pathway that cells use to protect DNA during replication. The findings, published Jan. 24 in the journal Molecular Cell, suggest that targeting this pathway could potentially increase the efficacy of cancer treatments.

‘Cells that fail to protect their genome will die,’ senior author said Zhongsheng You, PhD, Professor of Cell Biology and Physiology. “This entire pathway we found exists to protect the genome so that cells can survive in the face of replicative stress. Inhibitors of this pathway target the DNA replication process.” Combining it with chemotherapeutic drugs may make such drugs more effective.”

Replication stress occurs when a cell’s DNA replication machinery has trouble copying the genome. Certain stretches of DNA are inherently difficult to copy because they contain many repetitive sequences. Factors that damage DNA, such as radiation and toxic molecules, also cause replication stress, as does cancer-causing gene activation. Dozens of anticancer drugs, including widely used drugs such as cisplatin and doxorubicin, work by damaging DNA and increasing replication stress.

Study how cells protect their genomes during replication. Early in his career, he worked on his ATR-Chk1 genome protection pathway. This pathway regulates the cell division cycle and prevents stalled replication machinery from failing completely and causing DNA breaks. Over the past eight years, he and his team have painstakingly pieced together another previously unknown pathway of genome protection. This new research has put the final piece of the puzzle into place.

The process they found goes something like this: When the DNA replication machinery stalls, a protein called Exo1 that normally follows the machinery gets a little out of hand. Exo1’s job is to perform quality control by cutting out the erroneously copied pieces of DNA, but when the machine stops moving forward, Exo1 begins clipping haphazardly, severing pieces of DNA. cell. DNA is not normally found outside the nucleus, so the presence of DNA in the main part of the cell raises an alarm. Upon encountering a fragment of DNA, the sensor molecule triggers a cascade of molecular events including the release of calcium ions from the cellular organelle known as the endoplasmic reticulum. This shuts down Exo1 and prevents further genome dicing. until the mechanical problem is resolved.

This latest study describes the discovery of a DNA fragment as a warning signal that initiates an entire genome protection response. The study was led by lead author Dr. Shan Li, as a postdoctoral researcher and later as a staff scientist in You’s lab. Li is currently an assistant professor at Zhejiang University School of Medicine in Hangzhou, China. Co-author, graduate student Kong Lingzhen, also made important contributions to this 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 in cancer research.

“Now that we have a pathway, we want to see if we can target it for cancer therapy,” you said. Other cancers are replicative stressed by chemotherapeutic drugs, and because this pathway protects cells from replicative stress, blocking this pathway may improve a patient’s response to cancer treatment. I have.”

Some of the proteins in this pathway also play roles in other important biological processes such as immunity, metabolism, and autophagy, the process by which cells degrade unwanted substances.

“One of the most exciting things about this pathway is how it intersects with so many other pathways,” You said. “Although I have focused on cancer, much of this can also apply to autoimmune diseases. It is related to autoimmune diseases.We want to understand the relationship between this replicative stress response pathway and the innate immune response pathway.The work we are doing is very basic It is exciting to connect the dots between these basic processes and see how they relate to human health and disease.