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November 13, 2017

DNA Replication’s Got a Good Beat, and Cancer Can Dance to It

Source: Genetic Literacy Project

  • If cancer had ever been interviewed on American Bandstand about a new song, it might have echoed countless teenagers by saying, “It’s got a good beat and you can dance to it”—but only if a slow number had just been played. Cancer, it happens, has two left feet when it comes to DNA replication, which must proceed at a slow pace if cancer is to avoid tripping itself up.

    "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, Ph.D., a postdoc at the University of Copenhagen and the first author of a new study about the tempo of DNA replication. “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."

    The possibility that cancer cells could be killed by accelerating DNA replication was detailed November 10 in the journal Science, in an article entitled “Redox-Sensitive Alteration of Replisome Architecture Safeguards Genome Integrity.” According to the article, replication stress is prevented when cells take advantage of a mechanism that reduces replication speed.

    Essentially, this mechanism balances the pace of DNA replication with the availability of nucleotides, the DNA building blocks that are produced by an enzyme called ribonucleotide reductase (RNR).

    "We can see that these processes follow the same periodic rhythm,” asserted Jiri Lukas, Ph.D., senior author of the new study and a professor at the University of Copenhagen. “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.”

    By mapping the regulation of nucleotides, Prof. Lukas and colleagues determined that the flow of nucleotides follows the same rhythm as does DNA replication. When the flow of nucleotides is faster, cells can slow replication, allowing the processes to keep to the same time.

    “We find that perturbation of ribonucleotide reductase (RNR) in humans elevates reactive oxygen species (ROS) that are detected by peroxiredoxin 2 (PRDX2),” wrote the authors of the new study. “In the oligomeric state, PRDX2 forms a replisome-associated ROS sensor, which binds the fork accelerator TIMELESS when exposed to low levels of ROS.”

    When RNR is attenuated, ROS levels become elevated, disrupting oligomerized PRDX2 to smaller subunits, whose dissociation from chromatin enforces the displacement of TIMELESS from the replisome. This process, Prof. Lukas’ team explains, instantly slows replication fork progression, which mitigates pathological consequences of replication stress.

    “Thus, redox signaling couples fluctuations of dNTP [deoxynucleotide triphosphate] biogenesis with replisome activity to reduce stress during genome duplication,” the Science paper concluded. “We propose that cancer cells exploit this pathway to increase their adaptability to adverse metabolic conditions.”

    The cell reacts to even slight changes in the flow of nucleotides. If the production falters, a chemical signal consisting of ROS spreads the message to slow DNA. Slower DNA replication 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.

    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. Thus impeded cancer cells, which are particularly vulnerable to a high replication speed, would struggle to proliferate

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