Cutting edge microscopy technique leads to new insights in cancer

By Samantha Black, PhD, ScienceBoard editor in chief

November 1, 2019 -- New research published in the October 31 edition of Science debuts a new technique for creating high-resolution visual maps of the chromatin structure remodeling (RSC) complex to further understand its role in healthy and cancer cells. This research was led by Bradley Cairn, PhD, cancer researcher at Huntsman Cancer Institute and professor and chair of oncological sciences at the University of Utah.

Cellular components such as the RSC complex, an ATP-dependent chromatin remodeler family consisting of 17 subunits, are mutated in nearly one-fifth of all human cancers. These gene mutations can cause changes in gene expression which can lead to uncontrolled growth of cancer cells.

The RSC complex functions with multiple auxiliary subunits in vivo to provide regulation and targeting. The RSC and related complexes are crucial regulators of chromosome structure and gene expression. Once the RSC complex binds to the genome, it executes machine-like movements that expose segments of DNA in chromosomes, leading to the initiation of gene expression. Specifically, it employs DNA translocation to slide or eject the promoter +1 nucleosomes to extend NFRs, possibly to expose transcription start sites and promote transcription. Researchers set out to determine the structure of RSC bound to the nucleosome, in order to provide insights into RSC organization and function.

This study provides evidence that complex works in conjunction with the cellular machinery. Previous research using low-resolution modeling left questions of how the complex specifically interacted within the cell. Now, using sophisticated new cryo-electron microscopy techniques, the team was able to visualize the chromosomal structures in high resolution.

"The RSC complex plays an important role in both healthy and cancer cells," says Cairns. "Now, we can accurately visualize a high-resolution map of the RSC complex, including all of its components. We can see how the complex interacts with, and moves, chromosomes, and DNA. This provides crucial information that helps us understand how RSC-like complexes are involved in cancer."

Normal and mutated cell lines of the RSC complexes were compared to determine specific interactions other cellular components to provide insight into DNA translocation and promoter nucleosome repositioning by RSC. This data will allow scientists to elucidate the cellular mechanisms of mutated genes during cancer.

"This study has crucial implications for our ability to understand how chromosomal genes in healthy and cancer cells are exposed and expressed," said Cairns. "This type of information is a critical step in the processes that scientists use to develop new drugs and understand the genomic characteristics of a tumor."

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