DNA is generated from nucleotides by an enzyme called RNR. This study from the University of Copenhagen reveals how RNR's rhythm and presence of the right amount of nucleotides are aligned with the pace of DNA replication. The work was published last week in Science.
"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, corresponding author of the paper.
The research groups led by Chuaram Choudhary and Lukas have found that overall the cell reacts to small changes in the flow of nucleotides. If there are not enough nucleotides available, a chemical signal gets sent to the DNA replication sites to slow down. According to the research paper, this communication between nucleotide supply and DNA replication speed is possible because the DNA replication sites have a protein called PRDX2 to sense the chemical alert.
When PRDX2 protein is notified, it releases an accelerator called TIMELESS from the DNA which slows down the pace with which cell cope their DNA. Doing this allows the nucleotide production to catch up and get back in rhythm with DNA synthesis.
The researchers showed that they can deactivate the chemical signal that alerts the cells to problems with nucleotide production. Under these conditions, the cells cannot slow down the replication process, and the researchers propose that this would stop the 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, first author the study.