Like a monkey in the DNA jungle
A protein important in the fight against cancer must find cuts in our genome by swinging from one segment of DNA to another.
Our cells constantly withstand damage that can lead to breaks in the strands of our DNA. These cuts need to be fixed for the cell to stay healthy. When a break happens, one of the first responders to the scene is a protein known as PARP1. It binds to the ruptured strand (or strands) and then it recruits other repair agents to that location. But first, PARP1 needs to scan for cuts and notches amongst an overwhelming amount of DNA that is still intact. This is a complicated task, especially since the protein tends to bind both broken and unbroken DNA. How does it not stay ‘stuck’ on an undamaged portion of the genome?
Here, Rudolph et al. use a combination of biochemical techniques and cell biology to show that PARP1 travels through our genome by swinging from one DNA location to another, the way a child grabs onto monkey bars. One of the DNA-binding domains of PARP1, known as the WGR-domain, acts like an arm and initiates the movement by gripping onto a new segment of DNA. In fact, chopping off the WGR-domain or disabling it through mutations makes PARP1 worse at finding DNA breakages in the cell.
Unfixed DNA damage can lead to a cell becoming cancerous; ultimately, if the breakages keep accumulating, the cell does not survive. This makes PARP1 an important target for cancer treatment. Indeed, certain drugs already rely on trapping the protein so that tumor cells die. Understanding how cells cope with DNA damage and exactly how PARP1 works could help in the fight against cancer.
To find out more
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