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Scientists have made a major discovery on how cells repair broken DNA strands that could have interesting implications for cancer treatment.
Their study, published in Nature on Wednesday, revealed a brand new complex The new complex causes cancer cells to use a particular type of DNA repair system that is vulnerable to targeting by new drugs called PARP or platinum inhibitors. The historical study is the result of a collaboration between the University of Toronto, the Institute of Cancer Research of London, the Dutch Cancer Institute and the University of Toronto. Berne
. and monitor the treatment of patients with mutations in BRCA1, BRCA2 or other DNA repair genes.
"PARP inhibitors are very promising for the treatment of bad and ovarian cancer, but we have to derstand why they sometimes do not work, or stop working altogether," says Daniel Durocher a professor in the Department of Molecular Genetics and Principal Investigator in the Lunenfeld-Tanenbaum Research Institute at Sinai Health System. 19659002] "Learning more about how cancer eludes the inhibition of PARP by studying the basic mechanisms of DNA repair brings us closer to this goal, which will improve the way we treat some of the the most insoluble cancers. "
complex has also been found important to generate the right kind of antibodies during an immune response, and mutations could lead to immune-related disorders.
PARP inhibitors are extremely promising treatments because they benefit from a major vulnerability of certain cancers. a weakness in the ability of cancer cells to repair their DNA. Traditional platinum-based chemotherapy is also used in a more targeted way to take advantage of the weaknesses of DNA repair.
When it is intact, the newly discovered Shieldin complex contributes to this vulnerability by attaching to broken DNA, forcing cancer cells to attempt to repair their DNA in a way that makes them sensitive to PARP inhibitors and platinum chemotherapies
. But when mutations are introduced into the components of the complex, the researchers found that cancer cells grown in the laboratory and in mice were using a PARP inhibitor olaparib approved in the US and Europe for treatment ovarian and bad cancers with BRCA mutations, and looks promising against some prostate cancers – so the findings could have a significant impact on cancer treatment if mutations in the Shieldin complex result in a failure of clinical treatment
the complex, the international team of researchers badyzed bad cancer cells and mice that had mutations in the gene BRCA1
Read the search in Nature [19659011] They used state-of-the-art Crispr / Cas9 gene manipulation technology for genetic mutations that made the cells resistant to drugs. inhibitors of PARP, olaparib and talaoparib, as well as platinum chemotherapy.
Thanks to painstaking experiments, researchers were able to identify the main genetic mutations that led to drug resistance. these have had an effect on and have developed what these proteins did in the cells.
They found that the new complex is composed of newly identified proteins, now named SHLD1, SHLD2 and SHLD3.
found to attach to the ends of the broken DNA so that the "blunt ends" of the DNA must be glued directly – a faster and more messy way of repairing the DNA. DNA that can sometimes be necessary to make antibacterial When researchers introduced mutations in the Shieldin complex – which prevent it from forming and protecting the broken ends of the DNA – the cells are free to repair the DNA by a different method, which means that PARP inhibitors are no longer effective.
The study was funded by various organizations around the world, including the Canadian Cancer Society and the Canadian Institutes of Health Research, and Cancer Research UK and Breast Cancer Now in the United Kingdom
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