Cells diligently protect the integrity of their genome, as damage can lead to cancer or cell death. The genome – a cell’s complete set of DNA – is most vulnerable when it is 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 cells use to protect their DNA while it is being copied. The findings, published Jan. 24 in the journal Molecular Cell, suggest that targeting this pathway could potentially increase the potency of cancer therapeutics.
“A cell that cannot protect its genome is dying,” said senior author Zhongsheng Yu, PhD, professor of cell biology and physiology. “This entire pathway we found exists to protect the genome so the cell can survive replication stress. By combining inhibition of this pathway with chemotherapy drugs that target the DNA replication process, we can potentially make such drugs more effective.”
Replication stress occurs when the cell’s DNA duplication machinery has trouble copying the genome. Some stretches of DNA are inherently difficult to copy because they contain many repetitive sequences. DNA-damaging agents such as radiation and toxic molecules also cause replication stress, such as the activation of cancer-causing genes. Dozens of cancer drugs, including widely used drugs such as cisplatin and doxorubicin, work by damaging DNA and increasing replication stress.
You study how cells protect their genomes while they are being replicated. Earlier in his career, he worked on the ATR-Chk1 genome-protection pathway — a pathway that regulates the cell-division cycle and prevents stalled replication machinery from completely failing and causing DNA breaks. For the past eight years, he and his team have been painstakingly piecing together another previously unknown genome-protection pathway. With this new study, the final piece of the puzzle clicked into place.
The mechanism they discovered goes like this: When the DNA-like machinery stalls, a protein called Exo1 that normally runs behind the machine gets out of hand. Exo1’s job is to control quality by cutting off incorrectly copied pieces of DNA, but when the machinery stops moving, Exo1 starts randomly moving away, ripping off bits of DNA that then exit the nucleus and enter its nucleus. by doing DNA is not found outside the nucleus in normal cells, so its presence in the main part of the cell raises an alarm. Upon encountering a fragment of DNA, a sensor molecule triggers a cascade of molecular events, including the release of calcium ions from a cellular organelle known as the endoplasmic reticulum, which in turn shuts down Exo1, preventing it from further cleaving the genome. Until the equipment problem can be resolved.
This new study describes the discovery of DNA fragments as warning signals that set off whole-genome-defense responses. The study was led by first author Shan Li, PhD, as a postdoctoral researcher and then a staff scientist in U’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 contributed significantly 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 under development that can be repurposed for cancer studies.
“Now that we have the pathway, we want to know if it can be targeted to treat cancer,” You said. “Lung, ovarian and breast cancers are intrinsically under replicative stress. Replication is put under stress by other cancer chemotherapy drugs. This pathway protects cells from replication stress, so if we can block the pathway, it could improve patients’ response to cancer therapy.”
Several proteins in this pathway also play roles in other complex biological processes, including immunity, metabolism, and autophagy, the process by which cells break down their own unwanted material.
“One of the most exciting things about this path is how it intersects with so many other paths,” You said. “I’m focusing on cancer, but much of this could apply to autoimmune diseases as well. Two proteins we identified have been linked to chronic activation of the immune response and autoimmune disease. We want to understand the relationship between this transcriptional-stress response pathway and the innate immune response pathway. The work we do is very fundamental, and it’s exciting to connect the dots between these fundamental processes and see how they relate to human health and disease.”