Discovery vital to understanding cell damage in cancer and other illnesses
The body’s ability to detect and repair DNA errors that can occur during normal cell processes is essential to healthy human development. A new discovery by researchers at Mount Sinai’s Samuel Lunenfeld Research Institute released today in the prestigious journal Nature, uncovers a previously unknown link in the DNA repair process, offering a deeper understanding of how DNA repair mechanisms fail in diseases like cancer.
Senior Investigator Dr. Daniel Durocher
and his team of researchers at the Lunenfeld, including lead author Dr. Amelie Fradet-Turcotte, have discovered the function of a protein that is vital to the efficient repair of DNA damage. This protein, called 53BP1, responds to a unique ‘flare’ signal called ubiquitin (another protein involved in cellular regulation), when there is DNA damage present and then works together to accelerate the repair process.
“When cells encounter damage in their DNA, they must ring the alarm so that a team of repair proteins can rapidly mend the problem,” explains Dr. Amelie Fradet-Turcotte, a post-doctoral researcher at Mount Sinai’s Samuel Lunenfeld Research Institute. “Until now, we knew the alarm existed but we did not know how cells detected this signal. Understanding this missing link is very important for our understanding of cancer and other illnesses.”
The Nature paper
demonstrates how the protein 53BP1 protects the integrity of DNA by detecting two distinct marks at the site of DNA damage in the cell, and then helps direct repair of the damage, resulting in the re-joining of the broken DNA strands. When the DNA repair system is not functioning optimally in cells, mutations can go undetected and accumulate, potentially leading to abnormal growth and, eventually, tumours.
“Our bodies have these incredibly efficient systems that fix the damage in their DNA that occurs every day in millions of our cells,” says Dr. Daniel Durocher, who is also a Professor in the department of Molecular Genetics at the University of Toronto. “This fascinating process, which employs its own communication system, is central to life.”
In addition to being potentially harmful to normal cells, the process of DNA damage also has potential in the clinical treatment of cancer, such as in radiation therapy, by selectively damaging the DNA of tumour cells. This also means that the knowledge of DNA damage and repair processes can be harnessed to develop more efficient cancer therapies. However, the potential applications of this work are likely to be many years in the future.
Dr. Durocher and his team have made a series of seminal discoveries by studying how normal cells become cancerous and how healthy cells detect and repair damage to their DNA. His team’s most recent discovery builds on this research. In 2008, his team discovered a gene called RNF8, which helps to guide the protein BRCA1, associated with breast cancer, to damaged DNA so the cell can start making the necessary repairs. Dr. Durocher is the Thomas Kierans Research Chair in Mechanisms of Cancer Development and also holds the Canada Research Chair in Molecular Genetics of the DNA Damage Response.
This study was funded by the Canadian Institutes of Health Research and the Ontario Research Fund.