JAN 05, 2015 12:00 AM PST

Adds to our understanding about immune system's abilities

WRITTEN BY: Judy O'Rourke
While our immune system counts on the production of antibodies to spot and sap bacteria and viruses, it does not stockpile separate schematics for each of these specialized proteins as this would necessitate vast amounts of DNA. Our body instead assembles segments of sequence to create some 300 trillion options.

This process of combining (recombination) depends upon DNA being clipped by the enzyme RAG [recombination activating gene]. Producing these specialized immune system proteins, which allow the immune system to neutralize its targets. Researchers at Johns Hopkins, Baltimore, have found the mechanism that prevents RAG from uncontrolled clipping of DNA-which acts, in effect, like a safety bolt on a door.

Familiarity with the process that holds the enzyme in check may help us understand why its mutant forms can precipitate immunodeficiency and cancer.

"Recombination is essential for the immune system's ability to recognize and fight new enemies, but too much clipping can cause harmful chromosome rearrangements," says Stephen Desiderio, MD, PhD, director, Institute for Basic Biomedical Sciences, Johns Hopkins Medicine, professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, and the senior researcher for the study. "We now know that RAG has a built-in lock that prevents it from getting out of hand as it clips DNA."

A summary of the results, published in the journal Cell Reports is found here: bit.ly/1xv0lhJ

To streamline the system, each immune cell manufactures a single antibody after being activated. A segment of RAG, called the PHD, enforces this level of control, according to earlier findings from Desiderio's team.

The PHD binds to a chemical tag, called H3K4me3, which is found solely on DNA that is actively being rewritten as RNA, preventing RAG from recombining DNA that is not active. When the PHD segment was mutated and dysfunctional, RAG couldn't cut-however, when the PHD was cut out entirely, RAG worked alright. Desiderio's team sought out mutations that would deliver function back to the mutant PHD, and discovered that when 13 amino acids were deleted in front of the mutant PHD segment, RAG's clipping was superior.

Grad student Alyssa Ward, visualizes it thus: think of the PHD piece as the lock, H3K4me3 as the key, and the deleted piece is the bolt. So, H3K4me3 unlocks the PHD segment, which triggers the bolt, allowing the door to open (RAG to cut). Mutations in the PHD prevent the key from working-however, the door opens and closes easily if the lock or bolt are detached from the door.

These findings may be significant for other proteins that interact with DNA. "It was previously thought that H3K4me3 was simply a docking site for proteins," Desiderio says. "This study shows that it is also a key that activates them."

Image: Using electron microscopy, researchers observed IFI16 pathogen sensors lining up on pieces of DNA. [Photo credit: The Sohn Lab]
About the Author
  • Judy O'Rourke worked as a newspaper reporter before becoming chief editor of Clinical Lab Products magazine. As a freelance writer today, she is interested in finding the story behind the latest developments in medicine and science, and in learning what lies ahead.
You May Also Like
NOV 10, 2019
Drug Discovery & Development
NOV 10, 2019
Promising Results for New Vaccine Against Dengue Fever
Dengue fever is an illness transmitted by mosquito bites. Affecting around 390 million people per year, if left untreated, its mortality rate is 20%. Altho...
NOV 20, 2019
Immunology
NOV 20, 2019
Harnessing the Power of Natural Killer Cells to Fight Cancer
Manipulating the immune system’s population of natural killer cells could bolster therapies targeting cancer. A new study saw positive results invest...
DEC 05, 2019
Drug Discovery & Development
DEC 05, 2019
New Injection that Treats Peanut Allergy
Peanut allergies affect between 1 and 3% of the US population. Associated with a heightened risk of severe anaphylactic reactions, oral immunotherapy is th...
FEB 07, 2020
Neuroscience
FEB 07, 2020
Eating Fruits and Vegetables May Lower Alzheimer's Risk
New research has found that flavonols, a large class of compounds present in many fruits and vegetables, may be linked to a lower risk of developing Alzhei...
MAR 17, 2020
Immunology
MAR 17, 2020
What's the deal with SARS-CoV-2's spike protein?
Structurally, SARS-CoV-2 (the virus that causes COVID-19) are spherical shells consisting of a lipid membrane, with a core containing the virus’ gene...
MAR 29, 2020
Cell & Molecular Biology
MAR 29, 2020
Learning More About Boosting Immunity in Older Adults
Older adults are more susceptible to infections and don't generate a robust immune response after a vaccination....
Loading Comments...