Researchers have discovered that a key genetic repair protein also cleans up ‘traps’ left by another protein, its partner in genetic repair.
DNA is constantly getting damaged: the delicate strands that carry life’s genetic code take quite a beating as they jumble about in the course of their work. Errors can accumulate if left untreated, with fatal consequences — such as cancerous tumors — for the cell and the organism.
Two key proteins are involved in preventing the damage from getting out of hand: PARP — or poly ADP ribose polymerase — acts as a marker for a trouble spot, allowing XRCC1 — or X-ray repair cross-complementing protein 1 — to locate the damage and start repairs.
The repair functions of these two proteins have been known for some time. The importance of this has been recognised with the 2015 Nobel prizes for chemistry, as this knowledge allowed the development of anti-cancer drugs, known as PARP inhibitors, that disrupt the growth of certain kinds of tumours.
Although these key proteins had been identified, their precise roles were not well understood. It took a team of scientists at Tokyo Metropolitan University, the University of Sussex, and Kyoto University to revealed how exactly XRCC1 accomplishes its work — and it was a surprising discovery.
“PARP turns out to be something of a villain,” explained Kouji Hirota at Tokyo Metropolitan. “The spots it marks become ‘PARP traps’, which left un-repaired lead to disfunction and cell death.”
It seems that XRCC1 doesn’t just simply repair DNA, it goes about disarming PARP traps. The scientists compared cells without the XRCC1 gene to those without PARP as well as to still others which lacked both proteins. The team found that without XRCC1 on patrol, PARP traps accumulate like landmines.
“PARP exerts toxic effects in the cell and XRCC1 suppresses this toxicity,” Hirota elaborated.
The team aims to further explore these processes, with the goal of aiding development of future cancer treatments.
KyotoU’s Shunichi Takeda said: “These results indicate that XRCC1 is a critical factor in the resolution of PARP traps and may be a determinant of the therapeutic effect of PARP inhibitors used in the treatment of hereditary breast and ovarian cancer syndromes.”
Source: Kyoto University
Journal reference: Demin, A. A., et al. (2021) XRCC1 prevents toxic PARP1 trapping during DNA base excision repair. Molecular Cell. doi.org/10.1016/j.molcel.2021.05.009.
