Unprecedented: a team from Institut Curie discovers how DNA unzips at the time of replication

Since the discovery of the structure of the double DNA helix in 1953, the way in which double DNA strands unwind and deploy was an unsolved mystery.

This time we have just taken another step towards understanding the origins of life

Calmly explains Chunlong Chen, head of the Replication program and genome instability team at Institut Curie (CNRS UMR3244 / Institut Curie / Sorbonne University).

Chunlong, in collaboration with biologists from the University of Hong Kong (Yuanliang Zhai) and from the Hong Kong University of Science and Technology (Bik-Kwoon Tye and Shangyu Dang), has just published a major study in the journal Cell.

Each of our cells carries two meters of DNA inside it, which it must replicate at each cell division. For this to happen, our 23 pairs of chromosomes must open and separate into two strands to serve as a model for the DNA polymerase to synthesize complementary strands. Errors in this process are the cause of tumors. We knew that in eukaryotes (organisms whose cells possess a nucleus, like humans, animals, fungi and plants), the mechanism to initiate replication of DNA is based on the MCM2-7 gene family. The MCM2-7 then assemble to form a double-hexamer complex (DH), encircling the DNA along the chromosomes. This process, however, was still poorly understood.

This time, using multidisciplinary approaches, the team was able to clearly observe how the MCM2-7 complex destabilizes the DNA, allowing it to open for the first time, precisely at the junction of the two hexamers.

Imagine it like a zipper that separates the two notched edges

Says Chunlong Chen with a smile.

The team also discovered that the MCM2-7 DH are loaded on DNA on tens of thousands of sites through the human genome, which are mutually exclusive with transcriptionally active loci. When this initial structure is disrupted, the MCM2-7 DH can no longer assemble on the DNA. Then it is impossible for the DNA to replicate.

This unprecedented discovery gives hope of a new era for cancer treatments. The therapies currently available, particularly chemotherapy, kill replicating cells indiscriminately, whether they are normal or cancerous. Developing new targeted MCM2-7 treatments would help pause the replication of normal cells and specifically target the dividing cancerous cells, which would then be destroyed. More broadly, this progress adds a piece to the puzzle of the great enigma of this story.

An initial open structure (IOS) is formed upon binding of human MCM double hexamer (hMCM-DH) to origin DNA.