Mon. May 23rd, 2022


3D model of DNA. Credit: Michael Ströck / Wikimedia / GNU Free Documentation License

The DNA that lies tightly wound in almost every human cell is exposed to thousands of insults and damage from inside and out daily, which is why the human body has developed several very effective mechanisms to repair DNA damage.

“We have sophisticated mechanisms to repair DNA breaks, and when they fail, we end up with disease. We accumulate genomic instability, we accumulate mutations, and many diseases occur due to the cells’ inability to repair DNA,” says Raul Mostoslavsky. , MD, Ph.D., Scientific Co-Director of the MGH Cancer Center and Laurel Schwartz Professor of Oncology (Medicine) at Harvard Medical School.

Repairing DNA damage is a double-edged sword: When it goes awry, it can lead to diseases such as cancer and degenerative motor disorders, but it can also be used to treat many types of cancer using drugs that interfere with DNA’s ability to repair themselves. , which causes cancer cells to stop replicating and die.

Previous studies of DNA repair mechanisms were performed using systems developed by biochemists to purify proteins, but these systems have relatively low yields or “throughput,” explains Mostoslavsky.

“We decided to develop a high-throughput assay to try to identify repair factors in a more objective way. We ended up developing a unique microscope-based automated system to generate DNA damage and to collect information about proteins recruited to them. types of injury, he says.

With co-researchers at the National Cancer Research Center in Madrid and at other centers in the United States, Canada and China, Mostoslavsky and colleagues at MGH and Harvard have developed a very sensitive method for visualizing DNA repair mechanisms at work. Using the technique, they have identified nine new proteins involved in DNA repair, a finding that could help researchers develop new cancer drugs, as well as methods to improve the effectiveness of existing treatments.

They describe their technique – a combination of high-throughput microscopy and machine learning – in the journal Cell reports.

The investigators first developed a high-throughput microscopy test to analyze how proteins are attracted to or excluded from double-stranded DNA fragments. With this system, they generated a library of 384 mostly unknown factors and were able to identify which of these proteins are called to action when DNA damage occurs.

They then performed a proof-of-principle study, looking for a specific factor labeled PHF20 that is kept away from the site of DNA damage, and discovered that PHF20 is excluded because it may interfere with the recruitment of another critical DNA repair factor labeled 53BP1.

The systems developed by Mostoslavsky and colleagues, for example, could help improve the treatment of breast and ovarian cancer caused by mutations in the cancer susceptibility genes BRCA1 and BRCA2. These cancers are treated with a class of drugs known as PARP inhibitors that work by inhibiting a specific DNA repair factor.

Development of tools to visualize DNA repair like never before

More information:
Barbara Martinez-Pastor et al., Assessing Kinetics and Recruiting DNA Repair Factors Using High-Content Monitors, Cell reports (2021). DOI: 10.1016 / j.celrep.2021.110176

Provided by Massachusetts General Hospital

Citation: Newly discovered DNA repair mechanisms point to potential therapy targets for cancer and neurodegenerative diseases (2022, January 20) retrieved January 20, 2022 from .html

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