New Functions of Chromatin Remodeling Machines Discovered

Scientists at the Huntsman Cancer Institute have discovered new functions of a key cellular machine that regulates gene packaging and is mutated in 20% of human cancers. The study was published in Molecular Cell.

The team wanted to understand how the motor of chromatin remodeling machines are regulated. "These really are machines: they contain a 'gas pedal' and a 'clutch' that together control whether and how the motor moves the machine along the DNA. This new paper shows the gas pedal and clutch sit right on the motor, and the cancer-causing mutations localize to the clutch and gas pedal itself, making the motor hyperactive and unpackaging genes when it should not," said lead author Braid Cairns. The work reveals how factors in the cell can activate the machine to do its work at the right place and time.

Cairns and his colleagues used data on mutations in human tumors from the COSMIC cancer database, the largest cancer genomics database in the world, in order to study the human chromatin remodeling machine called BAF/PBAF. BAF/PBAF is mutated in 20% of all human tumors, 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 and how fast to run along the DNA, move nucleosomes, and open up genes for their activation. Notably, the team found a series of cancer mutations in an area of the hub that regulates the motor activity and thus ensures proper movement or removal of nucleosomes and proper gene expression. These mutations in the regulatory hub of the motor created a hyperactive and dysregulated motor that improperly opens up chromatin. The team's findings shed light on a key regulatory behavior of healthy cells and explain how a set of cancer-causing mutations promote cancer.