New research explains how the motor of an enzyme in DNA damage repair is switched on and off and how these processes might go awry in cancer. The work was published yesterday in Molecular Cell and comes from researchers at Uppsala University and the Francis Crick Institute.
Amplified in Liver Cancer 1 (ALC1) is an enzyme that contains a motor which is responsible for altering the structure and packaging of chromatin. It uses ATP as fuel and can allow chromatin to be "stretched" so that other proteins can access the DNA.
"What is special about this enzyme is that it also possesses a specific portion, a 'macro domain' that can recognize a type of polymer that accumulates at sites where DNA has been damaged. Thus it is involved in repairing damage to DNA," says Laura Lehmann, one of the researchers in the group.
By combining a variety of approaches, the researchers were able to map the molecular mechanisms that control the remodeling activity of the enzyme by its macro domain. They showed that the macro domain of the chromatin remodeler ALC1 physically interacts with its ATPase motor and that this effectively shuts off the motor's activity when it is not needed.
"It can be described as a molecular brake that switches off the motor when there is no DNA damage. When damage occurs, the macro domain binds to polymer chains at the damage site, which recruits the ALC1 enzyme to the site and simultaneously shifts its shape in such a way that the brake is released from the motor. Activated ALC1 could then make the damaged DNA accessible for repair processes," explains Sebastian Deindl, a corresponding author on the paper.
The work may help explain why several mutations reported in human cancer may compromise the "off switch" for the enzyme ALC1. The researchers also found that when some cancer mutations are introduced, they see a hyperactive, permanently "on" ATP motor.
"Such uncontrolled activity of ALC1 in the absence of DNA damage is expected to have severe consequences for the cell. Ultimately, a better molecular-level understanding of the mechanisms that control ALC1 activity may in the long term open up new horizons for therapeutic intervention strategies," says Deindl.