Complex cellular machine visualized to yield new insights in cancer

October 31, 2019

SALT LAKE CITY - Cellular machines that control chromosome structure, such as the RSC complex, are mutated in about one-fifth of all human cancers. Now, for the first time, scientists have developed a high-resolution visual map of this multi-protein machine, elucidating how the RSC complex works and what role it has in healthy and cancer cells. The study was co-led by Bradley Cairns, PhD, cancer researcher at Huntsman Cancer Institute (HCI) and professor and chair of oncological sciences at the University of Utah, along with Ning Gao, PhD, at Peking University and Zhucheng Chen, PhD, at Tsinghua University in China. The study was published today in the journal Science.

A process known as gene expression underlies the behavior of every cell in all living organisms. Gene expression provides cells with a blueprint that orchestrates their behavior, including growth, death, and responses to changes in the cellular environment. Gene expression is necessary for living healthy and cancer cells; however, cancer cells express genes that carry a defective set of instructions that often lead to uncontrolled growth. 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.

Nearly 20 years ago, Cairns discovered the RSC complex and later added to his findings by identifying many of its protein components and revealing its machine-like behavior. Now, Cairns and his colleagues have established how this complex works in conjunction with the cellular machinery. He believes these findings will yield highly significant insights into how certain cancers develop. "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."

Previous studies led to lower resolution models of the RSC complex, but many questions remained unanswered, including how the subunits of this complex assemble and interact with the chromosomal genome. Cairns and his colleagues, including lab members Cedric Clapier, PhD, and Naveen Verma built on existing knowledge using yeast cells, a classic model system to study chromosomes and gene expression. They utilized new and sophisticated microscopic techniques that allowed them to visualize chromosomal structures in high detail. Cairns and his colleagues were able to study the RSC complex in depth by developing numerous cell lines that contained both normal and mutated versions of the RSC complex. Next, their team studied yeast RSC using cryo-electron microscopy - a technology that has only become available in recent years. This tool allows scientists to view the architecture of large, sophisticated cell components at a high-resolution molecular level.

The scientists are now using this information to understand the RSC complex and its role in cancer further. "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."
-end-
This research was supported by the National Cancer Institute grants P30CA042014, R01CA201396, and U54 CA231652; Howard Hughes Medical Institute, Huntsman Cancer Foundation, the Ministry of Science and Technology of China, and the National Natural Science Foundation of China.

About Huntsman Cancer Institute:

Huntsman Cancer Institute (HCI) at the University of Utah is the official cancer center of Utah. The cancer campus includes a state-of-the-art cancer specialty hospital as well as two buildings dedicated to cancer research. HCI treats patients with all forms of cancer and is recognized among the best performing cancer hospitals in the country by U.S. News and World Report. As the only National Cancer Institute (NCI)-Designated Comprehensive Cancer Center in the Mountain West, HCI serves the largest geographic region in the country, drawing patients from Utah, Nevada, Idaho, Wyoming, and Montana. More genes for inherited cancers have been discovered at HCI than at any other cancer center in the world, including genes responsible for hereditary breast, ovarian, colon, head, and neck cancers, along with melanoma. HCI manages the Utah Population Database, the largest genetic database in the world, with information on more than 11 million people linked to genealogies, health records, and vital statistics. HCI was founded by Jon M. and Karen Huntsman.

Huntsman Cancer Institute

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.