Damaged DNA inside cells can lead to the development of cancer, neurodegenerative disorders and many other diseases. To fix the problem, organisms have evolved to rapidly tag a number of ‘repair proteins’ near the site of damage with chemical flags. This process, known as ADP-ribosylation (ADPr), acts like an alarm system to identify the place where help is needed.
So fundamental is ADPr to understanding how cells deal with DNA damage that some chemotherapy drugs, which have been designed to prevent key enzymes involved in the process from working, are already being used to treat certain types of breast, ovarian and prostate cancers. Yet the underlying molecular mechanisms of ADPr are still poorly understood – something that is limiting our ability to develop new, more effective treatments.
It was already known that ADPr flags attach to particular sites on proteins within damaged cells, but it was unclear exactly where. More recent studies have shown that ADPr flags attach to a number of amino acids – the building blocks of proteins.
The original aim of the EU-funded INVIVO_DDR_ADPR project was to map all the amino acid sites for ADPr flags in the worm Caenorhabditis elegans – an undertaking that promised to fully reveal the molecular mechanisms for repairing damaged DNA. But after the first set of experiments, the researchers discovered that ADPr flags can also attach to the amino acid serine. Overlooked for 50 years, this is an incredibly important aspect of the DNA repair process; if scientists can understand the regulatory networks that underlie this complex biological process, it will provide new insights for improved treatment of diseases that relate to DNA damage, including cancer.
‘It may seem like a small detail, but in the cell “factory” this is an important mechanism,’ says researcher Juan José Bonfiglio, from the INVIVO_DDR_ADPR research group co-ordinated by Ivan Matic at the Max Planck Institute for Biology of Ageing in Germany. ‘It’s like discovering a new letter in an alphabet you thought you knew – namely the alphabet the cell uses for sending vital internal messages.’
Improving DNA repair to treat disease?
Because this finding was so unexpected, the team altered some of the project’s specific aims to focus on this new discovery.
They went on to work out the molecular mechanism by which the ADPr signal is ‘written’ on to the amino acid serine and how it is then erased again. Their work has also shown that the flagging of serine plays a very important role in the cell’s response to DNA damage.
The team’s work has the potential to provide important insights for the improved treatment of diseases such as cancer, by opening up new possibilities to improve and increase the efficiency of the DNA repair machinery.
New tools for science
‘Our discovery revealed how important discoveries may be hidden in scientific “blind spots”,’ says Bonfiglio, who received funding through the EU’s Marie Skłodowska-Curie fellowship programme for this project.
The need to progress their research also forced the team to come up with novel tools, which have led to two patent applications. These include a new, first-instance approach to generating antibodies that are site-specific and enable detection of specific ADPr sites.
‘We’re convinced that these tools will be useful not only for our own projects but for the scientific community in general,’ says Bonfiglio.