Researchers exploit rhythm of DNA replication to kill cancer cells

New DNA is generated in human cells from tiny building blocks called nucleotides produced by an enzyme called RNR. Until now, we have not fully understood how exactly the RNR rhythm and the presence of right amount of nucleotides are aligned with the pace of DNA replication. Now, researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen have mapped the flow and regulation of nucleotides. The flow follows the same rhythm as replication of DNA does - and when it does not, the cells regulate the process to align the two.

"We can see that these processes follow the same periodic rhythm. We found a mechanism that instantly slows down DNA-replication when RNR, the nucleotide factory, gets out of that rhythm, but well before the nucleotide supply becomes critically low, says Jiri Lukas Professor and Executive Director at The Novo Nordisk Foundation Center for Protein Research.

Building blocks catching up

The research groups led by Professors Jiri Lukas and Chunaram Choudhary found that the cell reacts to even small changes in the flow of nucleotides. If the production falters, a chemical signal consisting of reactive oxygen species (ROS) spreads the message to slow down the DNA replication.

Their research paper; published today in the journal Science, reports that such communication between nucleotide supply and DNA replication speed is possible thanks to the fact that all sites in human genome that actively copy DNA contain a protein called PRDX2 that senses this chemical alert.

When this happens, the PRDX2 protein releases an accelerator called TIMELESS from the DNA, and this release slows down the pace with which cell cope their DNA. Slower DNA replications allows for the production of nucleotides to catch up and get back to the same rhythm with DNA synthesis. Because of this, there are almost always enough nucleotides to build the DNA, which is turn is critically important for the copying the healthy genomes without mistakes.

High speed kills cancer

This finding sheds light on several illnesses, but is especially important in relation to cancer. The researchers show that they can deactivate the chemical signal that alerts the cells to problems with nucleotide production. Under such conditions, cells cannot slow down the replication process, and the researchers propose that this would impede proliferation of cancer cells because they are particularly vulnerable to a high replication speed.

"We found that cancer cells copy their DNA rather slow, because they have abnormal genomes and replicating DNA has to overcome many obstacles. When we remove their ability to copy their genomes slowly, the cancer cells die because they cannot cope with too many bumps on their DNA templates," says Kumar Somyajit, Post.Doc and first author of the study.

Kumar Somyajit, Rajat Gupta, Hana Sedlackova, Kai John Neelsen, Fena Ochs, Maj-Britt Rask, Chunaram Choudhary, Jiri Lukas.
Redox-sensitive alteration of replisome architecture safeguards genome integrity.
Science, Vol. 358, Issue 6364, pp. 797-802. doi: 10.1126/science.aao3172.

Most Popular Now

GSK reaches agreement with Novartis to acquire ful…

GlaxoSmithKline plc (LSE/NYSE: GSK) today announces that it has reached an agreement with Novartis for the buyout of Novartis' 36.5% stake in their Consumer Healthcare Jo...

Canadian neuroscientists say daily ibuprofen can p…

A Vancouver-based research team led by Canada's most cited neuroscientist, Dr. Patrick McGeer, has successfully carried out studies suggesting that, if started early enou...

Merck partners with Medisafe to help improve medic…

Merck, a leading science and technology company, today announced a new collaboration with US-based Medisafe to help its cardiometabolic patients better manage medication ...

New immunotherapy for lung cancer shows promise of…

In a groundbreaking development, results from a recent clinical trial to treat lung cancer show that a novel immunotherapy combination is surprisingly effective at contro...

Boehringer Ingelheim and OSE Immunotherapeutics an…

Boehringer Ingelheim and OSE Immunotherapeutics, a biotechnology company focused on the development of innovative immunotherapies, have announced a collaboration and excl...

Personalized tumor vaccine shows promise in pilot …

A new type of cancer vaccine has yielded promising results in an initial clinical trial conducted at the Perelman School of Medicine at the University of Pennsylvania and...

Taking a standard prostate cancer drug with food b…

By taking a high-cost drug with a low-fat meal - instead of on an empty stomach, as prescribed - prostate cancer patients could decrease their daily dose, prevent digesti...

New targeted therapy schedule could keep melanoma …

Skin melanoma, a particularly insidious cancer, accounts for the vast majority skin cancer deaths and is one of the most common cancers in people under 30. Treatment for ...

Researchers identify chemical compound that inhibi…

An organic chemical compound shows effective antiviral activity against Ebola virus and several other viruses, according to a study led by Georgia State University. The r...

When drugs are wrong, skipped or make you sick: Th…

Rising drug prices have gotten a lot of attention lately, but the actual cost of prescription medications is more than just the dollars and cents on the bill. Researchers...

New class of drugs could help tackle treatment-res…

Researchers have discovered a new class of drug that has the potential to help cancer patients who no longer respond to existing therapies. The drug may not become availa...

Researchers propose key elements of antimicrobial …

Antimicrobial stewardship programs (ASPs) in hospitals play a vital role in managing the threat of antibiotic resistance. To be of maximum effectiveness, essential elemen...