Nature uses cryo-electron microscopy to advance breast and ovarian cancer research

"BRCA1-BARD1 is important for DNA repair
.

It is directly related to cancer, because hundreds of BRCA1 and BARD1 gene mutations have been found in cancer patients," the lead author of the paper, a structural biologist and biologist at the Mayo Clinic Chemist Dr.

In the cell, the complex of DNA and histones is compounded into so-called chromatin and packed into bundles called nucleosomes
.

DNA damage response proteins need to enter chromatin to repair damaged DNA

Cryogenic electron microscopy and nuclear magnetic resonance spectroscopy

"We used two techniques-cryo-electron microscopy and nuclear magnetic resonance spectroscopy-to understand how BRCA1-BARD1 is related to nucleosomes (repeating units of chromatin) at close to atomic resolution, and how BRCA1-BARD1 is How to modify chromatin," Dr.
Mer explained
.

Under a cryo-electron microscope, the purified BRCA1-BARD1 binds to nucleosomes, together called macromolecules, which are quickly frozen and then imaged with an electron microscope
.

Macromolecules are located in different ways in the sample, so the computer program evaluates all the positioning data to create a 3D structure

"We showed how BRCA1-BARD1 attaches ubiquitin to nucleosomes, but we also determined that BRCA1-BARD1 can recognize ubiquitin that has been attached to nucleosomes, which is a signal to break DNA," Mer Said the doctor
.

"We found an unexpected crosstalk.

The researchers made a video based on cryo-electron microscopy data showing where the protein complex interacts with the nucleosome (see link below)
.

From scientific discovery to patient care

Dr.
Mer and his team hope that the high-resolution images of BRCA1-BARD1 can help guide patient care and future cancer treatment in two ways: classify variants of unknown significance and guide drug development more accurately
.

"With these 3D structures, we should be able to convert some unknown mutations into mutations that may induce cancer," Dr.
Meyer said
.

"This work is also expected to have a long-term impact on drug development, because the 3D structure of BRCA1-BARD1 and our nucleosome complex may help design small molecules, for example, to inactivate BRCA1-BARD1

In addition to Dr.
Mer, the other authors of the paper are Dr.
Qi Hu; Dr.
Maria Victoria Botuyan; Dr.
Debiao Zhao; Dr.
Gao Feng Cui; and Ellie
.

The research was funded by the National Institutes of Health, the Mayo Clinic Cancer Center, the Mayo Clinic Biomedical Discovery Center, and the Ovarian Cancer Research Consortium, and was conducted at the Pacific Northwest Cryogenic Electron Microscopy Center and Mayo Cancer Research Consortium using cryo-electron microscopy and nuclear magnetic resonance instruments.

Journal Reference :

1. Qi Hu, Maria Victoria Botuyan, Debiao Zhao, Gaofeng Cui, Elie Mer, Georges Mer.