How the cell’s DNA replication machinery overcomes obstacles

2021

Challenge

DNA replication is required for organisms to grow and develop and to expand populations of stem cells that maintain tissues as we age. The machinery that copies a cell’s DNA, known as the replisome, must overcome numerous impediments that arise from toxins in the cell and outside in the surrounding environment, as well as alternative DNA arrangements. A particularly toxic and powerful block to DNA replication comes from the strong chemical links between strands of DNA that are introduced by cellular metabolites and common cancer chemotherapy drugs. However, technology to answer fundamental questions about how replisomes respond to this obstacle in living cells has, until now, been unavailable.

Advance

IRP researchers led by Michael M. Seidman, Ph.D., developed a novel technique to visualize what happens when structures called replication forks, which form during DNA replication, encounter a chemical link between DNA strands. Previously, these links were considered an insurmountable block to replisomes copying the DNA. However, the IRP scientists unexpectedly discovered a major new pathway through which DNA synthesis continues past the obstacle. Furthermore, the researchers discovered that there are two forms of the replisome: one that replicates the active parts of the genome that can be accessed without impediment early in the ‘synthesis’ phase of the cell’s life cycle; and another, occurring later in that phase of the cell’s life cycle, that works on the inactive sections of the genome containing DNA sequences that can form problematic structures and stall DNA replication.

Impact

Failure to overcome challenges to DNA replication can cause a wide range of problematic consequences, including cancer-causing mutations, genome rearrangement, cell death, and the activation of inflammatory pathways that underlie many of the maladies of aging. As such, the IRP researchers’ discoveries about how replisomes respond to obstacles are key to the development of strategies to address two important but opposing goals. First, replisome-blocking drugs are commonly used in cancer chemotherapy, and their findings could aid the development of treatments that enhance replisome failure at these blocks in tumor cells, which would increase therapeutic efficacy. Second, the insights from their research could accelerate the creation of therapeutic interventions that help the replisome overcome obstacles in normal, healthy cells, thereby suppressing an instigator of inflammatory pathways that cause so much damage during aging.

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