Molecular-level mapping shows how cells repair damaged DNA, safeguard genetic information

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Katheryn Meek (view larger image)

Cell division takes place in the human body several million times per day. With each split, DNA molecules — because of their inherent instability — are highly susceptible to damage, which can lead to genetic mutations. Add in external factors such as UV radiation and carcinogenic substances, and the odds of DNA damage increase even further. MSU AgBioResearch immunologist and molecular geneticist Katheryn Meek has been studying DNA repair for just over three decades. This type of basic research has implications in areas ranging from human medicine to agriculture and biotechnology.

“DNA is the blueprint for all living organisms; thus all organisms have evolved numerous mechanisms to ensure maintenance of an exact copy of their genomes for propagation,” she said. “Given its importance to life, it is somewhat surprising that evolution has allowed DNA to be so sensitive to various forms of damage, including oxidation, hydrolysis and methylation.”

Meek explained that an entire host of molecular systems are continuously monitoring and repairing DNA at any given time, and that the pathways used to make these fixes are essentially the same in plants, animals and humans. Her laboratory studies how DNA double strand breaks (DSBs) are repaired. She said DNA breaks, whether single-stranded or double-stranded, can lead to unfortunate outcomes, such as cancer.

“Thus, the maintenance of genome integrity is essential not only for organism survival but also for the inheritance of traits by offspring,” she said. There are two major pathways — nonhomologous end joining (NHEJ) and homologous recombination (HR) — that repair DSBs in all organisms. Meek focuses on a large enzyme called the DNA dependent protein kinase (DNA-PK). It initiates NHEJ because it recognizes broken DNA ends and then targets other NHEJ factors to the site of damage. Emerging data implicate DNA-PK as a central regulator of DNA end access. Meek said ongoing studies are looking at how DNA-PK regulates DNA end access to promote end joining with minimal sequence information loss. Additionally, Meek said, it is becoming apparent that DNA-PK may affect other repair pathways, potentially by limiting access of DNA ends to repair factors. This may have particularly important side effects in species that express very high levels of DNA-PK, and may explain the remarkable variation between species when the gene encoding this enzyme is mutated.

Meek is particularly excited about her recent discovery regarding T and B lymphocytes, the cellular components of adaptive immunity. During development of these cells, a gene shuffling mechanism is utilized that allows the cells to make cell surface receptors and serum molecules (antibodies) that recognize invading pathogens. However, this gene shuffling mechanism requires the introduction of DNA double strand breaks and is inherently dangerous for the cell and the organism. Thus, lymphocytes are particularly susceptible to translocations and mutations that cause cancer. She recently completed an experiment that lends insight into the mechanism of how lymphocytes prevent these genetic mutations by using protein factors to help guide how these intentional DNA breaks are repaired.

“B cell and T cell leukemia is pretty common because lymphocytes make mistakes during this gene shuffling process,” Meek said. “There is a whole set of protein factors that help carefully guide those DNA breaks exactly into the pathway they’re supposed to go. If that pathway is not available, then the cell should just die; but sometimes these misrepaired DNA breaks can result in a cell being changed from a normal cell into a cancer cell. We know that there is a mechanism to prevent this, but we don’t understand really how it works. Now I have a hint of how that works.”

Meek has written a paper based on the study findings and has submitted it for publication. She said the work may help to better understand the mechanism that promotes immune system development. Because the system relies on DNA repair in the gene shuffling process that allows people and animals to become immune to invading pathogens, animals and people that have genetic defects in this DNA repair pathway have no immune system. They have a genetic disease called SCID (severe combined immune deficiency), or the “bubble boy disease.”

“In the past, my lab has defined the genetic mutations that cause this type of immunedeficiency disease in dogs and horses,” she said. “These were useful findings because they helped us better understand the biology of how this pathway works. But now, other groups have discovered or genetically engineered similar mutations in pigs. Since these animals are completely immunedeficient, it is possible to implant human cells into them. This may allow researchers to directly study human cells — either cancerous or normal — in a large animal. These studies have previously been primarily limited to mouse models; having a large animal model opens up really incredible possibilities.”

In addition to medical advancements, Meek said DNA repair is also an integral part of agricultural biotechnology. In this process, scientists select for gene variance to achieve desired traits, such as increased yield or improved food quality.

“Being able to manipulate the DNA and really understand how DNA repair works helps scientists more efficiently manipulate the genomes of organisms they’re interested in — for instance, making more sustainable crops,” she said. “There are many, many laboratories trying to manipulate genomes to make better beef. The things I do in my lab make it easier for those things to happen.”

Meek said that understanding how DNA repair works is the first step in being able to genetically manipulate organisms, whether the efforts are to find ways to fight cancer or to produce higher quality foods with fewer environmental impacts. The importance of studying DNA repair was recently supported by one of the most prestigious scientific awards of its kind. The 2016 Nobel Prize in Chemistry was awarded to Thomas Lindahl, Paul Modrich and Aziz Sancar — three scientists who all examine how cells repair DNA base damage and safeguard genetic information.

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