Keeping DNA repair under control
A human protein called ARH3 — which is lost in some cancers — switches off a ‘DNA damage’ signal when the DNA has been repaired.
Inside cells, genetic information is stored within molecules of DNA. If any of the DNA becomes damaged, the cell has a suite of proteins that can help to repair the DNA. Many of these proteins act as signals that alert the cell to the presence of damaged DNA. One such signal involves adding a molecule called ADPr onto specific proteins that are near the damaged section of DNA.
There are several enzymes that can attach ADPr molecules to proteins and other enzymes known as ADP-ribosylhydrolases can halt the signal by removing the ADPr molecules. Together, these two groups of enzymes control how strong the ADPr signal is, how long it lasts, and therefore control the DNA repair process.
Proteins are made up of building blocks called amino acids. Previous studies have shown that ADPr molecules can be attached to several different amino acids including glutamate, aspartate and cysteine. Specific ADP-ribosylhydrolase enzymes are known to be responsible for removing ADPr molecules from these amino acids. In 2016, a group of researchers found that ADPr can also be added to an amino acid called serine. However, it is not known if cells are able to remove ADPr molecules from serine, or which ADP-ribosylhydrolases might be involved.
Pietro Fontana, Juan Bonfiglio, Luca Palazzo and colleagues — including some of the researchers involved in the earlier work — used biochemical techniques to investigate if any human enzymes are able to remove ADPr molecules that have been attached to serines on proteins. The experiments reveal that the serine ADPr signal increases after DNA damage, before reducing over time. However, in human cancer cells that lack an ADP-ribosylhydrolase known as ARH3, the serine ADPr signal persists after DNA damage. This suggests that adding ADPr molecules to the amino acid serine is a key signal that controls DNA repair and that ARH3 is the main enzyme responsible for erasing this signal.
Drugs that inhibit some of the enzymes that attach ADPr molecules to proteins are used to treat some breast, ovarian and prostate cancers. Therefore, understanding how cells remove these signals from proteins may aid the development of new therapies for these conditions. The next steps following on from this work are to find out more about the structure of ARH3 and to understand how cells that lack this enzyme behave.
Read the eLife research paper on which this eLife digest is based: “Serine ADP-ribosylation reversal by the hydrolase ARH3” (Jun 26, 2017).
