As part of an international research effort, SciLifeLab researchers from Karolinska Institutet have revealed a previously unknown strategy utilized by cancer cells to survive radiation damage. Caspase-activated DNase (CAD), which normally breaks up DNA during apoptosis, is hijacked by tumor cells and tricked into protecting them against radiotherapy.
According to the report, published in Science, tumor cells activate CAD (an endogenous nuclease) when irradiated. The introduction of new, controlled DNA damage by CAD enables cancer cells to spend more time repairing initial irradiation-induced DNA damage.
SciLifeLab Fellow Simon Elsässer and SciLifeLab researcher Jiri Bartek (KI) were part of an international team of scientists from Denmark, Sweden, Canada and Switzerland, led by Claus Storgaard Sørensen at the University of Copenhagen.
“While normal cells usually pause their division cycle at the so-called G1 phase control point, this mechanism is mostly defective in cancer cells. Therefore, the main option to prevent catastrophic cell division with broken chromosomes, which would kill the dividing cells, is to stay at the other, G2 phase checkpoint, just before the cells start dividing”, says Jiri Bartek.
The many CAD-made breaks ‘tell’ the tumor cells to wait until they repair both the more dangerous DNA breaks caused by radiotherapy, and the easy-to repair but numerous CAD-made ones. In this way, self-inflicted breaks basically help to prolong the duration of the G2 pause, thereby providing the tumor cells with time needed to heal their DNA wounds before resuming their cell division”, says Jiri Bartek.
The study further shows that inhibition of CAD activity makes cancer cells vulnerable to damage from radiation, not normal cells, making it a potential therapeutic target.
Simon Elsässer’s group was able to map the single-stranded DNA breaks inflicted by CAD, and found that it’s activity was not randomly targeting the genome, but concentrated on specific regions.
“With CAD-inflicted DNA damage following a discernible pattern, we hope to investigate in the future how the cell targets and contains this potent endogenous nuclease activity.” says Philip Yuk Kwong Yung, postdoctoral fellow in Simon Elsässer’s lab.
The research at Karolinska Institutet was funded by Vetenskapsrådet and ERC