||Researchers at the University
of Pennsylvania School of Medicine have discovered a unique
molecular pathway that detects and selectively eliminates
defective messenger RNAs from red blood cells.
||Knowing how this specific surveillance
system works can help researchers better understand hereditary
diseases, in this case, thalassemia, a form of anemia, which
is the most common genetic disorder worldwide.
||The results appear in the most recent
issue of Nature Structural and Molecular
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine have discovered a unique molecular pathway that
detects and selectively eliminates defective messenger
blood cells. Other such pathways – known as surveillance
pathways – operate in a more general way, in many cell types.
Knowing how this specific surveillance system works can help researchers
better understand hereditary diseases, in this case, thalassemia,
a form of anemia, which is the most common genetic disorder worldwide.
The results appear in the most recent issue of Nature
Structural and Molecular Biology.
Cells have developed surveillance mechanisms that identify and destroy
abnormal RNAs. Mistakes in a cell’s reading of RNA into protein can lead to the production of an abnormal protein, and this can result
in abnormal cell function or death.
The form of thalassemia studied by the Penn group is caused by a mutation that allows the cell’s ribosome to read too far, making a protein
that is too long. Thalassemias result from an underproduction of hemoglobin proteins – the oxygen carrying molecule in blood – hence
the anemia. The particular mutation they study is carried by millions
of people in Southeast Asia and is a major a cause of fetal loss
and disease in adults. Specifically in this study they show how far the
ribosome has to read into the RNA to trigger mRNA destabilization.
Several surveillance pathways have been identified over the last few
years that recognize specific types of mutations in RNAs. For example,
the most well-described pathway is one that recognizes nonsense
mutations that result in an RNA that makes a protein that is too
muscular dystrophy and cystic
fibrosis are examples of hereditary
diseases that result from nonsense mutations.
“We describe a surveillance pathway that targets RNA that is only
found in red blood cells,” says senior author Stephen
A. Liebhaber, MD, Professor of Genetics and Medicine. “More general surveillance
pathways are in all cells. The specificity of this particular surveillance
pathway has not been previously observed and predicts that there’s
something quite unusual about how RNAs are handled in red blood cells.
We’re interested in how this specific surveillance system works
in red blood cells because such understanding will increase our knowledge
of how these cells make high levels of hemoglobin and how defects in
this system could contribute to genetic disorders and possibly be reversed.”
“This type of surveillance pathway that is regulated at the tissue
level could also exist in other highly specialized cells,” says
first author Jian Kong, PhD, Senior Research Investigator. “Investigating
the mechanism of this pathway may help in understanding a wider range
of genetic disorders.”
Liebhaber is looking forward to further analysis of this surveillance
pathway in order to determine why it is specific to red cells and to
define the corresponding steps in gene expression in the red cell that
are so unusual. Such information should lead to new ideas on how to manipulate
this system in a variety of blood diseases.
The research was funded by the National
Heart, Lung, and Blood Disease Institute.
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