JAN 12, 2023 4:55 AM PST

Clumpy RNA Can Cause Major Problems for Cells

WRITTEN BY: Carmen Leitch

The nucleotide bases of our DNA are read in triplets, and three nucleotides together, called a codon, represents an amino acid that can be used to make a protein. In 1991, researchers found that several disorders including Fragile X syndrome, are caused by repeat sequences in certain genes. These repeats might happen several times or hundreds, which can cause instability in the genome, changes in affected proteins, and many other problems. Scientists have associated a variety of diseases with trinucleotide repeat expansions.

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To create proteins, coding sequences of DNA are transcribed into RNA by cells. When an excessive number of repeats appears in a gene, they can also be found in the corresponding RNA. Some of the nucleotides in those expanded RNA molecules may stick together, and RNAs that contain many repeats can tangle together and jumble up.

Those tangled RNAs can then form clumps in the nuclei of cells. The clumpy RNAs deform the shape of the nucleus, as well as disrupting the movement of materials in and out of the nucleus. They may trap other molecules, interfering with their function and eventually, causing cell death. However, the RNA clumps are not a cause of major problems for cells.

If the clumpy RNAs can migrate to the cytoplasm of the cell, they form gel-like clumps there too. They could be used to create an abnormal protein that harms the cell more seriously. These sick RNA sequences can confound the cellular machinery that produces proteins from RNA, because it cannot find the correct signals for where to start and stop the protein. This can lead to the production of aberrant proteins, which can also clump together and lead to more issues.

The findings have been reported in the Proceedings of the National Academy of Sciences (PNAS).

"We see a stark difference in toxicity between cells where that RNA is retained in the nucleus, where we see almost no toxicity, versus the cells where the RNA is exported into the cytoplasm, undergoes translation into proteins, and forms these clumps," said study co-author Michael Das, a graduate student in the lab of Whitehead Institute Member Ankur Jain.

In the cytoplasm, the RNA clumps can trap proteins that bind to RNA. RNA-binding proteins have been known to go to the wrong place in the cell in repeat expansion disorders. The study authors suggested that cytoplasmic RNA clumps are the cause.

When the researchers stopped the cells from translating RNA molecules with repeat expansions into protein, or stopped the clumpy RNA from leaving the cell, the clumps stopped forming in the cytoplasm, and cells were not seriously damaged.

In this study, the researchers did not use a fixation technique that involves formaldehyde, which may have been the reason why the RNA clumps have now been revealed, but have not been observed before this. Now that the researchers are able to see them, they will be confirming these findings in cells that have been collected from patients. They also want to know if this mechanism is occurring in other disorders that are linked to repeat expansions.

Sources: Whitehead Institute for Biomedical Research, PNAS

About the Author
Bachelor's (BA/BS/Other)
Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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