Researchers discover previously unknown ways cells protect their genomes during replication – Zoo House News
Cells are eager to protect the integrity of their genomes because damage can lead to cancer or cell death. The genome — a cell’s complete set of DNA — is most vulnerable while being duplicated 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 while it’s being copied. The results, published Jan. 24 in the journal Molecular Cell, suggest that targeting this pathway could potentially increase the effectiveness of cancer therapeutics.
“A cell that cannot protect its genome will die,” said senior author Dr. Zhongsheng You, 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 could potentially make such drugs 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 repeating sequences. Factors that damage DNA, such as radiation and toxic molecules, also cause replication stress, as does activation of cancer-causing genes. Dozens of anticancer drugs, including widely used drugs like cisplatin and doxorubicin, work by damaging DNA and increasing replication stress.
They study how cells protect their genomes while being duplicated. Earlier in his career, he worked on the ATR-Chk1 genomic protection pathway – a pathway that controls the cell division cycle and prevents a blocked replication machinery from completely malfunctioning and causing breaks in DNA. Over the past eight years, he and his team have meticulously pieced together another previously unknown way to protect the genome. With this new study, the final piece of the puzzle has clicked into place.
Here’s the process they discovered: when the DNA duplication machinery falters, a protein called Exo1, which normally follows behind the machinery, gets a little out of control. Exo1’s job is to perform quality control by snipping out miscopied pieces of DNA, but when the machinery stops moving forward, Exo1 begins snipping away at random, splitting off pieces of DNA that are then transported out of the nucleus and into the main part enter the cell. DNA is not found outside the cell nucleus under normal conditions, so its presence in the main body of the cell sets off an alarm. Upon striking a fragment of DNA, a sensor molecule triggers a cascade of molecular events, including the release of the calcium ion from a cell organelle, the endoplasmic reticulum, which in turn shuts down Exo1, preventing it from further dissecting the genome until the problem with the machine is fixed can be.
This latest study describes the discovery of DNA fragments as the red flag that triggers the entire genome protection response. The study was led by first author Shan Li, PhD, as a postdoctoral fellow and then as a tenured 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 important 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 could be reused for cancer studies.
“Now that we have the path, we want to know if it can be targeted for cancer treatment,” You said. “Lung, ovarian and breast cancers are inherently under replication stress. Other cancers are put under replication stress by chemotherapy drugs. This signaling pathway protects cells from replication stress. So if we could block the signaling pathway, it could improve patients’ response to cancer therapies. “
Some of the proteins in this pathway also play roles 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 path is how it intersects with so many other paths,” she said. “I’ve focused on cancer, but a lot of that could apply to autoimmune diseases as well. Two of the proteins we identified have been implicated in chronic activation of the immune response and autoimmune diseases. We want to understand the relationship between this replication – stress response pathway and the innate immune response pathway. Our work is very fundamental, and it’s so exciting to connect the dots between these fundamental processes and see how they relate to human health and disease.”