Building bridges: PARP enzymes bring broken DNA together
Date:
September 16, 2020
Source:
St. Jude Children's Research Hospital
Summary:
Researchers capture the structure of PARP enzymes at work, leading
to a new understanding of DNA repair that may aid cancer treatments
targeting the process.
FULL STORY ========================================================================== Scientists at St. Jude Children's Research Hospital have identified the structure of double-strand DNA break repair by PARP enzymes. The findings
show that PARP2 can bridge the gap, bringing two broken DNA ends together.
==========================================================================
The study also provides insight into the mechanisms that underlie PARP activation and the catalytic cycle, which may aid in understanding
resistance to cancer drugs that inhibit PARP. The work appears as an
advance online publication today in Nature.
"We expected that PARP would bind to DNA and modify chromatin to recruit
other DNA repair factors," said corresponding author Mario Halic,
Ph.D., of St. Jude Structural Biology. "Quite unexpectedly, we found
that the PARP enzyme itself is bringing two broken DNA ends together."
DNA is constantly damaged and repaired. This can be naturally occurring
or due to exposure to DNA damaging agents like some chemotherapies used
to treat cancer. PARP is a family of enzymes known by scientists to be
involved in several key cellular processes including DNA repair. However, exactly how PARP inhibitors interact with DNA and chromatin to accomplish
this process was unknown.
The researchers used cryogenic electron microscopy to capture the
structure of the PARP enzymes bound to DNA. Their findings showed that
the enzyme can draw the ends of broken DNA together. The study may have important implications for understanding resistance to drugs that inhibit
the activity of PARP.
PARP inhibitors are a class of drugs used to treat breast, ovarian and
prostate cancers among others. These drugs work by stopping PARP enzymes
from repairing DNA that has been damaged by chemotherapy. By stopping DNA repair, the drugs can help facilitate cancer cell death. Unfortunately, currently available PARP inhibitors are subject to resistance.
"We now have a better understanding of the complex role PARP enzymes play
in DNA repair," said first author Silvija Bilokapic, Ph.D., of St. Jude Structural Biology. "The mechanisms of PARP activation and catalytic cycle
we identified help explain how resistance to PARP inhibitors occurs and
could help in the development of more effective cancer treatments."
========================================================================== Story Source: Materials provided by
St._Jude_Children's_Research_Hospital. Note: Content may be edited for
style and length.
========================================================================== Journal Reference:
1. Silvija Bilokapic, Marcin J. Suskiewicz, Ivan Ahel & Mario Halic.
Bridging of DNA breaks activates PARP2-HPF1 to modify
chromatin. Nature, 2020 DOI: 10.1038/s41586-020-2725-7 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2020/09/200916113532.htm
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