Newly discovered DNA repair mechanisms point to potential therapy
targets for cancer and neurodegenerative diseases
Investigators have identified nine new factors involved in the process of
DNA repair that is critical to the health of human cells

Date:
January 20, 2022
Source:
Massachusetts General Hospital
Summary:
Faulty DNA damage repair can lead to many types of
cancer, neurodegenerative diseases, and other serious
disorders. Investigators have developed high-throughput microscopy
and machine learning systems that can identify and classify DNA
repair factors. The investigators have identified nine previously
unknown factors involved in the process of cellular DNA repair.



FULL STORY ========================================================================== Faulty DNA damage repair can lead to many types of cancer,
neurodegenerative diseases, and other serious disorders. Investigators
have developed high- throughput microscopy and machine learning systems
that can identify and classify DNA repair factors. The investigators
have identified nine previously unknown factors involved in the process
of cellular DNA repair.


==========================================================================
The DNA that lies tightly coiled in nearly every human cell is subjected
to thousands of insults and injuries from within and without daily, which
is why the human body has evolved multiple highly effective mechanisms
for repairing DNA damage.

"We have in place exquisite mechanisms to repair DNA breaks, and when
those fail, we end up with disease. We accumulate genomic instability, we accumulate mutations, and many diseases happen because of the inability
of cells to repair DNA," says Raul Mostoslavsky, MD, PhD, scientific co-director of the MGH Cancer Center and the Laurel Schwartz Professor
of Oncology (Medicine) at Harvard Medical School.

DNA damage repair 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 exploited to treat many forms of cancer using drugs that interfere with DNA's ability to fix itself, thereby causing cancerous
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," Mostoslavsky explains.

"We decided to develop a high-throughput assay to try to identify
repair factors in a more unbiased way. We ended up developing a unique microscope- based automatic system to generate DNA damage and to collect information on proteins that are recruited to these types of damage,"
he says.

With co-investigators at the National Cancer Research Center in Madrid
and at other centers in the U.S., Canada and China, Mostoslavsky and
colleagues at MGH and Harvard have developed a highly sensitive method
for visualizing DNA repair mechanisms at work. Using the technique,
they have identified nine new proteins that are involved in DNA repair,
a finding that can help researchers develop new cancer drugs, as well
as methods for improving the effectiveness of existing therapies.

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-strand DNA breaks. With this system they generated a library of 384 mostly unknown
factors and were able to identify which of these proteins are called
into action when DNA damage occurs.

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

The systems Mostoslavsky and colleagues developed could, for example,
help improve the treatment of breast and ovarian cancers 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 particular DNA repair factor.

The work is supported by MGH, the National Institutes of Health, the
Spanish Ministry of Science and Innovation, the Carlos III Institute of
Health, the Marie Curie COFUND FP7, European Research Council, and the
Natural Sciences and Engineering Research Council of Canada.

========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Barbara Martinez-Pastor, Giorgia G. Silveira, Thomas L. Clarke,
Dudley
Chung, Yuchao Gu, Claudia Cosentino, Lance S. Davidow, Gadea Mata,
Sylvana Hassanieh, Jayme Salsman, Alberto Ciccia, Narkhyun Bae,
Mark T.

Bedford, Diego Megias, Lee L. Rubin, Alejo Efeyan, Graham Dellaire,
Raul Mostoslavsky. Assessing kinetics and recruitment of DNA repair
factors using high content screens. Cell Reports, 2021; 37 (13):
110176 DOI: 10.1016/j.celrep.2021.110176 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220120103403.htm

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