Scientists Solve Mystery of How and When DNA Replicates

A research team led by Florida State University scientists has demonstrated that there are specific points along the DNA molecule that control replication. The study appears in the journal Cell.

Sima et al found that cis-regulatory elements control the 3D compartmentalization, architecture of the genome, and replication timing in a CTCF-independent manner. Image credit: Sima et al, doi: 10.1016/j.cell.2018.11.036.

In cells, DNA and its associated material replicate at regular intervals, a process essential to all living organisms. This contributes to everything from how the body responds to disease to hair color.

DNA replication was identified in the 1950s, but since then researchers have come up short trying to understand exactly how this process was regulated.

“It’s been quite a mystery. Replication seemed resilient to everything we tried to do to perturb it,” said study senior author Professor David Gilbert, a researcher in the Department of Biological Science at Florida State University.

“We’ve described it in detail, shown it changes in different cell types and that it is disrupted in disease. But until now, we couldn’t find that final piece, the control elements or the DNA sequences that control it.”

Professor Gilbert and colleagues examined a single segment of the DNA in the highest possible 3D resolution and saw three sequences along the DNA molecule touching each other frequently.

They then used a gene editing technology called CRISPR to remove these three areas simultaneously.

And with that, they found that these three elements together were the key to DNA replication.

“Removing these elements shifted the segment’s replication time from the very beginning to the very end of the process,” Professor Gilbert said.

“This was one of those moments where just one result knocks your socks off.”

In addition to the effect on replication timing, the removal of the three elements caused the 3D structure of the DNA molecule to change dramatically.

“We have for the first time pinpointed specific DNA sequences in the genome that regulate chromatin structure and replication timing,” said study first author Jiao Sima, also from the Department of Biological Science at Florida State University.

“These results reflect one possible model of how DNA folds inside cells and how these folding patterns could impact the hereditary materials’ function.”

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Jiao Sima et al. Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication. Cell, published online December 27, 2018; doi: 10.1016/j.cell.2018.11.036