Success Story

Seminal Discovery of DNA Repair Process of Cells Made at the Lunenfeld-Tanenbaum Research Institute

A vital discovery in our understanding of cell damage has been made at Mount Sinai’s Lunenfeld-Tanenbaum Research Institute: a repair protein. This new knowledge will add insight as to what goes awry, on a cellular level, in diseases like cancer.

DNA errors can, and do, happen during normal cell processes, but our bodies have the remarkable ability to detect and repair these errors in healthy human development. We now know considerably more about this crucial repair process, thanks to a team of researchers at Mount Sinai Hospital’s Lunenfeld-Tanenbaum Research Institute led by Senior Investigator Dr. Daniel Durocher, a Professor in the department of Molecular Genetics at the University of Toronto who holds the Canada Research Chair in Proteomics, Bioinformatics and Functional Genomics.

The Lunenfeld-Tanenbaum team has discovered that a protein, called 53BP1, responds to a unique ‘flare’ signal called ubiquitin, when there is DNA damage present and then works together to accelerate the repair process.

DNA Manipulation

“Our bodies have these incredibly efficient systems that fix the damage in their DNA that occurs every day in millions of our cells,” explains Durocher. “This fascinating process, which employs its own communication system, is central to life,” he adds.

This new research, the findings of which were published in the esteemed journal Nature, facilitates a deeper understanding of how DNA repair mechanisms fail in diseases like cancer in which abnormal cells divide without control and are able to invade other tissues – a process which is referred to in the scientific world as genomic instability.

Lunenfeld Team Tackling the Big Question: Why Cells Become Cancerous

The discovery of the DNA repair proteins was borne of Durocher’s primary research focus; the overarching goal of his lab is to understand how normal cells can become cancerous. Since genome instability is a hallmark of cancer, his lab is studying DNA repair, DNA replication and cell cycle checkpoints, the “gate keepers” of the genome.

Dr. Daniel Durocher
Dr. Daniel Durocher, Mount Sinai’s Lunenfeld-Tanenbaum Research Institute. Photograph courtesy of the research institute.

Durocher and his team have already had considerable success in this field of 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.

Understanding the Missing Link

The Nature article 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 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. Amélie Fradet-Turcotte, lead author of the Nature article and post-doctoral researcher at the Lunenfeld. “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,” she adds.

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.

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.

Durocher emphasizes, however, the potential applications of this work are likely to be many years in the future.

To read the Nature article, published in July 2013, “53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark,” go to: http://bit.ly/1nsp6zw. To read the press release from the Lunenfeld, go here: http://bit.ly/Wf2ZYa.

This study was funded by the Ontario Research Fund and the Canadian Institutes of Health Research.