Researchers discover new key cell machine functions in cancer

Reviewed by Emily Henderson, B.Sc.November 19, 2020

Scientists from Utah have discovered new functions of a key cellular machine that regulates the packaging of genes and is mutated in 20% of human cancers. The study was published today in print in the journal Molecular cell.

Genes are segments of cellular DNA, and the gene packaging is called chromatin. Genes are tightly packed when not activated and then unpacked by chromatin remodeling machines when genes need to be activated.

Mutations in chromatin-regulating machines are a significant cause of cancer and other human diseases, as mutant chromatin regulators unpack and improperly express genes, which disrupts the normal growth, identity and development of cells.

Chromatin remodeling machines have been a long-standing focus of Brad Cairns, PhD, lead author of the study, who discovered the first chromatin remodeling machine in 1996. Cairns is a scientist at the Huntsman Cancer Institute ( HCI) and professor and president of oncology sciences at the University of Utah (U of U).

Cairns Lab works to understand how chromatin affects gene expression in humans and other organisms and provides instructions for cell growth, identity and development. An important aspect of this work is to better understand the role of chromatin in cancer and other diseases.

The main component of chromatin are nucleosomes, which are similar to spheres on which DNA is wrapped like a string, explaining why chromosomes look like pearls on a string under a powerful microscope. Cairns and colleagues wanted to know how these spheres are moved or removed from DNA to unpack and expose genes.

Previous work has shown that chromatin remodeling machines have a motor-like component that drives the machine along the DNA, disrupting the nucleosome spheres. The fuel for the cellular engine is called ATP, a chemical produced in cells.

When properly tuned, the engine ensures that the right genes are properly unpacked. However, when the engine is improperly adjusted, the wrong genes are decompressed and cancer or improper development results.

The Cairns team wanted to understand how the car’s engine is tuned. “These are really machines: they contain a ‘gas pedal’ and a ‘clutch’ which together control whether and how the engine moves the car along the DNA.

This new article shows that the accelerator pedal and clutch are located right on the engine, and cancerous mutations are located in the clutch and the accelerator pedal itself, making the engine hyperactive and unpacking genes when it shouldn’t. ” reveals how the factors in the cell can activate the machine to do its job in the right place and time.

Cairns and his colleagues used mutation data in human tumors from the COSMIC cancer database, the largest cancer genomics database in the world, to study the human chromatin remodeling machine called BAF / PBAF. BAF / PBAF mutated in 20% of all human cancers, including pancreatic cancer, gastric cancer and melanoma.

They studied these human mutations using yeast as a model system. This analysis revealed a structural hub that tells the motor when to engage (the clutch) and how fast to run along the DNA (the accelerator pedal), move nucleosomes, and open genes for their activation.

Specifically, the team found a series of tumor mutations in an area of ​​the hub that regulates motor activity and thus ensures correct movement or removal of nucleosomes and correct gene expression. These mutations in the motor regulation center have created an overactive and dysregulated motor that improperly opens chromatin.

The team’s findings shed light on key regulatory behavior of healthy cells and explain how a range of cancerous mutations promote cancer.