DNA repair discovery could improve biotechnology

Date:
March 2, 2023
Source:
Michigan State University
Summary:
A team of researchers has made a discovery that may have
implications for therapeutic gene editing strategies, cancer
diagnostics and therapies and other advancements in biotechnology.


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FULL STORY ==========================================================================
A team of researchers from Michigan State University's College of
Veterinary Medicine has made a discovery that may have implications for therapeutic gene editing strategies, cancer diagnostics and therapies
and other advancements in biotechnology.


========================================================================== Kathy Meek, a professor in the College of Veterinary Medicine, and collaborators at Cambridge University and the National Institutes
of Health have uncovered a previously unknown aspect of how DNA
double-stranded breaks are repaired.

A large protein kinase called DNA-PK starts the DNA repair process; in
their new report, two distinct DNA-PK protein complexes are characterized,
each of which has a specific role in DNA repair that cannot be assumed
by the other.

"It still gives me chills," says Meek. "I don't think anyone would have predicted this." Meek's findings are published in Molecular Cell,a
high-impact journal that covers core cellular processes like DNA repair.

How DNA double-stranded breaks are repaired DNA, the blueprint of
life, is shaped like a helix; however, DNA is surprisingly easy to
damage. Ultraviolet light, for example, and many cancer therapies
including ionizing radiation and other specific drugs can all cause damage
to DNA. Sometimes, only one of the two strands break. Because the DNA is
still held together by the second strand, cells can repair the DNA fairly easily -- the cells just copy the information from the second strand.

It is more difficult for cells to repair DNA damage when both strands
are broken. Information in the form of nucleotides can be lost and
must be added back in before the DNA ends are rejoined. If a cell has
multiple DNA double- stranded breaks, the DNA ends can be joined with
the wrong partner. This type of mistake is often associated with many
types of cancers.

Double-stranded breaks also can be more difficult to repair if
DNA-damaging agents cause chemical modifications at the DNA ends. Damaged
DNA ends are often referred to as "dirty" ends.

DNA-PK can help repair DNA double-stranded breaks in one of two ways. For breaks with missing information, it can target enzymes that can fill in
missing nucleotides -- sort of like a needle and thread stitching the
DNA back together. For "dirty" ends, DNA-PK recruits enzymes that can
cut off the damaged DNA so that the ends can be rejoined.

This much was already known, but a key question remained unanswered in
the scientific literature -- until now: how does DNA-PK know whether to
fill in or cut off ends at a double-stranded break? Discovery of two
DNA-PK complexes: Fill in and cut off Meek's team and their collaborators previously published structural studies that revealed two different
DNA-PK complexes, called dimers. While many molecular geneticists already suspected that DNA-PK helps hold DNA ends together during the rejoining process, many wondered why there would be two dimers, instead of just one.

In their new study, Meek and her collaborators discovered that the two
distinct DNA-PK dimers have different functions; one complex recruits
enzymes that fill in lost information, while the other activates cutting enzymes that remove "dirty" ends. The team also discovered that repair
efficacy depends on equilibrium between the two dimers.

* RELATED_TOPICS
o Health_&_Medicine
# Genes # Human_Biology # Forensics
o Matter_&_Energy
# Organic_Chemistry # Biometric # Microarrays
o Computers_&_Math
# Computational_Biology # Encryption #
Information_Technology
* RELATED_TERMS
o Drug_discovery o Gene_therapy o Cervical_cancer o
BRCA1 o Breast_cancer o Biopharmaceutical o Stem_cell o
Energy_(healing_or_psychic_or_spiritual)

========================================================================== Story Source: Materials provided by Michigan_State_University. Original
written by Emily Lenhard. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Christopher J. Buehl, Noah J. Goff, Steven W. Hardwick, Martin
Gellert,
Tom L. Blundell, Wei Yang, Amanda K. Chaplin, Katheryn Meek. Two
distinct long-range synaptic complexes promote different
aspects of end processing prior to repair of DNA breaks by
non-homologous end joining. Molecular Cell, 2023; 83 (5): 698 DOI:
10.1016/j.molcel.2023.01.012 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/03/230302114017.htm

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