Study reveals a role for jumping genes during times of stress
Only a percentage of human DNA codes for proteins, and about half of the rest of the genome is made up of what used to be called "junk" sequences that can copy into RNA or DNA and jump from one place to another. Previous research by researchers at Massachusetts General Hospital (MGH) had revealed a critical role for one of these jumping genes in times of stress. In new research published by the same group in the Proceedings of the National Academy of Sciences, the researchers report a surprising new property of this jumping RNA.
Sequences that jump from one place to another in the genome are more formally known as transposable elements, and their role in health and disease is not fully understood. But it has long been suspected that they are more than just parasitic elements that do not function properly. In their original study, Jeannie Lee, MD, PhD, a researcher in the Department of Molecular Biology at the MGH, and her colleagues found that one of these transposable elements - a short and very abundant nuclear element (SINE) called B2 in mice (ALU in humans) - produces an RNA that is cleaved when combined with a protein called EZH2. However, at the time, they didn't know how the RNA is cut. Researchers are now making the striking discovery that B2 and ALU cut themselves.
Until four decades ago, it was thought that only proteins could make enzymes and only enzymes could cut nucleic acids, the building blocks of DNA and RNA. But in 1982, researchers showed that RNAs can also function as enzymes - and these RNAs are called ribozymes - a discovery that led to the Nobel Prize in Chemistry in 1989. Today, 15 classes of ribozymes have been described, but they are mostly found in bacteria and viruses. Very few are known in mammals such as humans, and their functions are mostly unclear.
Since B2 and UAL are so abundant in our cells, the discovery of the Lee group marks a new turning point in the history of ribozymes. "B2 and LAU are present in hundreds of thousands of copies in our DNA and are massively expressed during stress. That's a staggering amount of ribozyme activity," said Lee. The team found that B2 and ALU are normally silent, but when subjected to heat or other forms of stress, they become activated. In addition, their RNA cutting activity is enhanced by interaction with the EZH2 protein.
Lee noted that cells are continually challenged by stress, and a rapid response can mean the difference between life and death. "The articulation of the induction of stress-related genes to self-cutting RNA seems very adaptive," she said. "No new synthesis of gene products would be required, and instead the critical event would be the recruitment of a protein factor, EZH2, which already exists inside the cells and is ready to be mobilized."
The results may have important clinical implications for helping the body respond to stress, such as in the development of infections, cancer or autoimmune diseases.
