U of T scientists uncover DNA ‘shield’ with crucial roles in normal cell division, the immune system and cancer
Scientists have made a major discovery about how cells repair broken strands of DNA that could have exciting implications for the treatment of cancer.
Their study, published in Nature on Wednesday, uncovered a brand new protein complex in cells that shields broken DNA ends and controls the way in which it is repaired.
The new complex pushes cancer cells to use a particular type of DNA repair system that is vulnerable to targeting by new drugs called PARP inhibitors or platinum-based chemotherapies.
The landmark study was a result of collaboration between the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, the University of Toronto, The Institute of Cancer Research, London, The Netherlands Cancer Institute and the University of Bern.
The discovery could lead to tests to direct and monitor treatment for patients with mutations in BRCA1, BRCA2 or other DNA repair genes.
“PARP inhibitors hold great promise for breast and ovarian cancer treatment, but we must understand why they sometimes don't work, or stop working altogether,” says Daniel Durocher, a professor in the department of molecular genetics and senior investigator in the Lunenfeld-Tanenbaum Research Institute at the Sinai Health System.
“Knowing more about how cancer evades PARP inhibition by studying basic DNA repair mechanisms brings us a big step closer to this objective, which will improve how we treat some of the most intractable cancers."
The newly named "Shieldin" complex was also found to be important for generating the right type of antibodies during an immune response, and mutations could lead to immune-related disorders.
PARP inhibitors are hugely promising treatments because they take advantage of a major vulnerability of some cancers – a weakness in the ability of cancer cells to repair their DNA. Traditional platinum-based chemotherapies are also being used in a more targeted way to take advantage of DNA repair weaknesses.
When intact, the newly discovered Shieldin complex was found to contribute to this vulnerability by attaching to the broken DNA, forcing cancer cells to attempt to repair their DNA in a way that makes them susceptible to PARP inhibitors and platinum chemotherapies.
But when mutations are introduced in the components of the complex, the researchers found that cancer cells grown in the lab and in mice used an alternative way to repair DNA and quickly became resistant to PARP inhibitors.
The PARP inhibitor drug olaparib is approved in the U.S. and Europe for treating ovarian and breast cancers with BRCA mutations, and looks promising against some prostate cancers – so the results could have a wide impact on cancer treatment if mutations in the Shieldin complex are shown to lead to treatment failure in the clinic.
To uncover the complex, the international team of researchers analyzed breast cancer cells and mice that had mutations in the gene BRCA1.
They used cutting-edge Crispr/Cas9 genetic manipulation technology to search for gene mutations that caused cells to become resistant to the PARP inhibitor drugs olaparib and talaoparib, as well as the platinum chemotherapy cisplatin.
Through painstaking experiments, the researchers were able to pick out key gene mutations that led to drug resistance, which proteins these had an effect on, and work out what these proteins did in cells.
They found the new complex is composed of newly identified proteins, now named SHLD1, SHLD2, and SHLD3.
In healthy cells, the complex was found to attach to the ends of broken DNA so that the "blunt ends" of the DNA have to be stuck back together directly – a quicker, messier way of repairing DNA that can sometimes be necessary for making antibodies during immune responses.
When the researchers introduced mutations into the Shieldin complex – which stop it from forming and protecting broken DNA ends – cells are free to repair DNA via a different method, and this means PARP inhibitors are no longer effective.
The study was funded by a variety of organizations worldwide, including the Canadian Cancer Society and the Canadian Institutes of Health Research, and Cancer Research UK and Breast Cancer Now in the U.K.