Molecule biologists from Memorial Sloan Kettering Cancer Center (MSK) have unexpectedly captured the first detailed picture of the process driving cellular replication in human cells. The findings offer fresh new insight into the basic processes of human biology.
In the work, published in the journal Science, the team of MSK researchers utilized cryo-electron microscopy (cryo-EM) to investigate a DNA structure called G-quadruplex (G4 for short) which have recently gained attention as potential targets for cancer therapeutics.
“The DNA double helix is one of the most recognizable molecular structures in science,” said Sahil Batra, PhD, a research scholar in the Sloan Kettering Institute. “But DNA can actually exist in multiple shapes, and G-quadruplexes are one of them. There are drugs being developed to target G4s in cancer cells, but the mechanisms underlying G4s’ harmful effects are not clear — which is one of the reasons we are studying them.”
The findings of the study provide new insight into how secondary DNA structures, specifically G4s, can block replication.
“What these cryo-EM images showed us is that the G4 structure can get trapped — like an obstacle on the monorail track — inside the center of the ring-shaped protein complex called the CMG helicase that serves as the engine for unwinding the strands,” said Benjamin Allwein, a graduate student in the Sloan Kettering Institute.
“If these obstacles always led to an irreversible stall, we would never have successful cellular division,” added Batra. “So this will also help us learn more about mechanisms by which DNA gets repaired, modified, and corrected during replication. Problems in these processes are associated with a number of diseases, including cancer and neurodegeneration.”