The DNA that is tightly wound around almost every human cell is exposed to thousands of injuries and injuries both internally and externally every day. As a result, the human body has evolved several highly effective mechanisms for repairing DNA damage.
“We have an exquisite mechanism for repairing DNA breaks, and if they fail, we get sick. We accumulate. Genome instability, We accumulate mutations and many diseases occur because cells are unable to repair DNA, “Raul Mostoslavsky, MD, Ph.D., Co-Director of Science at the MGH Cancer Center and Professor of Oncology, Laurel Schwartz (Medicine). .. Says. At Harvard Medical School.
DNA Damage Repair is a double-edged sword: If it doesn’t work, it can lead to diseases such as cancer and degenerative movement disorders, but many forms of cancer with drugs that interfere with the ability of DNA to self-repair. It can also be used for treatment, which causes cancer cells to stop replicating and die.
Previous studies of DNA repair mechanisms have been performed using systems developed by biochemists to purify proteins, but these systems have relatively low yields or “throughput”, and Mostoslavsky explains.
“We decided to develop a high-throughput assay to identify repair factors in a more unbiased way. Ultimately, to generate DNA damage and collect information about the proteins used in these types. We have developed our own microscope-based automated system. Damage, “he says.
Together with collaborators from the National Cancer Center in Madrid and other centers in the United States, Canada, and China, MGH and Harvard’s Mostoslavsky and colleagues have developed a sensitive method for visualizing working DNA repair mechanisms. did. They use this technology to identify nine new proteins involved in DNA repair, discoveries that help researchers develop new anticancer drugs, and ways to improve the effectiveness of existing therapies. did.
They describe their technique (a combination of high-throughput microscopy and machine learning) in a journal. Cell report..
Researchers first developed high-throughput microscopy to analyze how proteins are attracted to or eliminated from double-stranded DNA breaks. Using this system, they were able to generate a library of 384 almost unknown factors and identify which of these proteins would act when DNA damage occurred.
They then performed a principle-based empirical study following one specific factor labeled PHF20 that was kept away from the site of DNA damage and mobilized another important DNA repair factor labeled 53BP1. We have discovered that PHF20 is excluded because it can interfere with.
A system developed by Mostslavsky and colleagues may help improve breast treatment, for example. Ovarian cancer Caused by a mutation in cancer Susceptible genes BRCA1 and BRCA2.These cancers are treated with a class of drugs known as PARP inhibitors that work by inhibiting specific DNA. repair element.
Barbara Martinez-Pastor et al, Assessment of DNA Repair Factor Dynamics and Mobilization Using High Content Screens, Cell report (2021). DOI: 10.1016 / j.celrep.2021.110176
Massachusetts General Hospital
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