Cancer Cells Slow Down DNA Replication
Cancer cells are able to slow down the process of DNA replication to account for their abnormal genomic features, and this may provide a novel point of attack for future anti-cancer therapies, according to a new study. The research, published in Science last week, demonstrates how cancer cells utilise pre-existing cellular mechanisms to reduce the rate of replication fork progression so that the abnormalities in their genomes can be successfully replicated. Speeding up replication once more results in cancer cell death and thus may be able to act as a therapeutic pathway in the future.
“We found that cancer cells copy their DNA rather slowly, because they have abnormal genomes and replicating DNA has to overcome many obstacles,” said Kumar Somyajit, PhD, first author of the study and PostDoc at the University of Copenhagen. “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.”
In all cells, the rate of DNA replication needs to be matched to the rate at which new nucleotides are produced by ribonucleotide reductase (RNR). In order to do this, healthy cells utilise a biochemical mechanism that signals DNA replication enzymes (such as DNA polymerase) to slow down when the supply of free nucleotides is declining. The mechanism ensures that the level of free nucleotides in the cell never becomes critically low and DNA replication can continue smoothly.
In this study, the team found that cancer cells were using the same mechanism to slow down DNA replication so that the abnormalities in their genomes could be mimicked in the daughter DNA strands. Their paper describes how when RNR output is lowered, meaning that there are fewer free nucleotides available, the cells elevate the levels of reactive oxygen species (ROS) in response. These ROS can then be detected by peroxiredoxin 2 (PRDX2), which in turn forms a replisome-associated ROS sensor and binds to the replication fork accelerator, TIMELESS.
Binding TIMELESS was found to instantly slow down the replication fork progression, reducing the pace of replication. In healthy cells, this allows the quantity of free nucleotides to increase once more, but in cancer cells it means that their mutated DNA can be correctly replicated.
Using this information, the team also attempted to speed up replication in cancer cells once more by targeting this signalling system. They found that they were able to ‘turn off’ the warning that resulted in TIMELESS binding, and thus could increase replication speed once more. The resulting replication stress caused the cancer cells to die.
It may be possible in the future to utilise this approach for new cancer therapies, although this is still early work. By targeting the rate of DNA replication, it may be difficult for cancer cells to develop resistance, as the mechanism is so vital to their reproduction process.