Researchers reveal how DNA unzipping machine MCM2-7 complex works, shedding lights on cancer therapy
An initial open structure (IOS) is formed upon binding of human MCM double hexamer (hMCM-DH) to origin DNA. Image modified from original illustration of Li et al, 2023 Cell 186, 1-14. Credit: Cell (2023). DOI: 10.1016/j.cell.2022.12.008

A research team led by Dr. Yuanliang Zhai from the School of Biological Sciences, The University of Hong Kong has discovered a new mechanism of the human MCM2 The findings were published in a scientific journal.

There is a single fertilized egg in the mother's uterus. The egg grows into our multicellular body. The blueprints of genetic information are accurately replicated during each cell division. Each cell has around 2 meters of DNA in it's nucleus. Our body will synthesise more than a light year's length of DNA of 10 16 meters over the course of 70 years. The DNA duplex needs to be melted first and then separated into two single-stranded templates for DNA polymerases to make complement strands. Misregulation of this process can cause serious consequences.

The Assistant Professor of HKU School of Biological Sciences said that it was important to understand the mystery of life.

How the DNA duplex is initially melted has been a long standing question for biologists. Professor Bik-Kwoon Tye at Cornell University identified the minichromosome maintenance protein complex (MCM) genes from wine brewing yeast as the ones responsible for unzipping the DNA duplex. The catalytic core of the unzipping machine is served by the products of six MCM genes.

To initiate DNA replication in cells, the MCM2-7 complex needs to be assembled into a head-to-head double hexamer. Only a small subset of the assembled MCM2-7DHs will be transformed into robust replicative heli cases. The initial opening of duplex DNA was thought to be caused by the presence of MCM2-7DH. The underlying mechanism wasn't known.

The research team wanted to use a cutting-edge technology to see the atomic details of the MCM2-7DH, which are millions of times smaller than the resolution limit of human eyes.

The first cryo-EM structure of MCM2-7DH isolated from yeast was published in the journal Nature. The captured DNA was not stable enough to tell the state of the duplex.

The researchers were able to determine the structure of the MCM2-7DH from cultured cells. This high-resolution structure shows a clear picture of how the MCM2-7 complex messes with the genes.

The team found that the MCM2-7DHs are loaded onto the human genome at tens of thousands of sites. When this initial open structure is disturbed, a complete suppression of DNA replication initiation can be achieved.

Dr. Shangyu Dang, Assistant Professor of Division of Life Science, HKUST, said that the study shows the importance of collaboration. The fundamental biological questions need to be answered with the help of research groups.

Several cancer drugs have been found to target the replication of genes. The drugs that are available kill all dividing cells because they don't work well with cancer cells. Concerns about the specificity of these drugs are raised. Normal cells will be arrested in the first growth phase, or withdraw from the cell cycle into theresting phase, if there is an alternative. It is possible to use inhibition of replication initiation as a novel and effective cancer fighting strategy.

The findings in this study give high-resolution structural and mechanistic information on the human pre-initiation complex that can be used to develop nontoxic anticancer drugs.

The human pre-renewal complex is an open complex.

Journal information: Cell , Nature