A team of researchers from Michigan State University’s College of Veterinary Medicine has made a discovery that may have implications for gene editing therapeutic strategies, cancer diagnosis and therapy, and other advances in biotechnology.
Kathy Meek, a professor in the College of Veterinary Medicine, and collaborators from the University of Cambridge and the National Institutes of Health have uncovered a previously unknown aspect of how DNA double-strand breaks are repaired.
A large protein kinase called DNA-PK initiates the DNA repair process; in their new report, two distinct DNA-PK protein complexes are characterized, each with 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 it.
Meek’s findings are published in Molecular Cell, a high-impact journal that covers fundamental cellular processes such as DNA repair.
How DNA double-strand breaks are repaired?
DNA, the blueprint of life, is shaped like a helix; However, DNA is surprisingly easy to damage. For example, ultraviolet light and many cancer therapies including ionizing radiation and other specific drugs can cause DNA damage. Sometimes only one of the two strands breaks. Because the DNA is still held together by the second strand, cells can repair the DNA relatively 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 before the DNA ends can join again. If a cell has multiple DNA double-strand breaks, the DNA ends may be joined to the wrong partner. This type of error is often associated with many types of cancer.
Double-strand breaks can also be more difficult to repair if DNA-damaging agents cause chemical modifications at the ends of the DNA. Damaged ends of DNA are often referred to as “dirty” ends.
DNA-PK can help repair DNA double-strand breaks in one of two ways. For breaks with missing information, it can target enzymes that can fill in the missing nucleotides — sort of like a needle and thread connecting DNA back together. For “dirty” ends, DNA-PK recruits enzymes that can cut the damaged DNA so the ends can rejoin.
This was already known, but a key question remained unanswered in the scientific literature: how does DNA-PK know whether to fill in or cut off the ends at a double-strand break?
Discovery of two DNA-PK complexes: Complement and cut
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 colleagues discovered that two distinct DNA-PK dimers have different functions; one complex recruits enzymes that fill in the lost information, while the other activates cutting enzymes that remove “dirty” ends. The team also found that the efficiency of repair depends on the balance between the two dimers.
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