FMRP Protein Helps Prevent DNA Damage, Maintain Genome Stability, Study Finds
According to investigators, these findings may help shed new light on the molecular processes underlying fragile X.
The study, “Replication Stress Induces Global Chromosome Breakage in the Fragile X Genome,” was published in the journal Cell Reports.
In normal circumstances, FMRP controls the production of several other proteins in the cytoplasm — all material found inside cells, apart from the nucleus — by interacting with the messenger RNA (mRNA) that cells use as a template molecule to generate proteins.
However, studies have also shown that FMRP can be found inside the nucleus, the small compartment that stores a cell’s genetic information. Yet, besides working as a shuttle to help transport mRNAs from the nucleus to the cytoplasm, the exact function of FMRP in nuclei remains unclear.
FMRP also has associated with cellular response mechanisms to DNA damage, which might help explain its presence in cells’ nuclei. However, it is still unknown if cells lacking the protein actually experience more or less DNA damage.
Here, an international group of investigators hypothesized that low levels of FMRP might increase genome instability — that is, lead to the accumulation of a high number of mutations in DNA. Of note, the genome is the complete set of genetic information in an organism.
To test this hypothesis, the team analyzed how fibroblasts, or connective tissue cells, and blood cells responded to external sources of DNA damage, which are known triggers of genomic instability. Both the fibroblasts and blood cells were derived from fragile X patients and healthy individuals, who served as controls.
After administering aphidicolin, a compound that prevents cells from making copies of their DNA, the scientists found that cells derived from patients accumulated more than twice the number of DNA double-strand breaks (DSBs) than those obtained from controls. This was observed in both cell types, and confirmed that the genome of cells lacking FMRP is naturally less stable.
DSBs are a type of DNA damage in which the DNA’s double strand is broken, preventing cells from making copies of that part of the genetic sequence.
In addition, the investigators found that in cells derived from the fragile X patients, DSBs tended to occur near R-loops — DNA-RNA hybrids that are formed when an RNA molecule binds to the chromosome region from which it originated, leading to a displaced single strand of DNA.
The scientists also showed that by forcing patient cells to produce a functional version of FMRP, the number of DSBs associated with R-loops decreased. However, when the cells were forced to produce a mutant form of the protein (I304N mutant) that is known to cause fragile X, this beneficial effect was lost.
“These results suggest that FMRP is a genome maintenance protein that prevents R-loop accumulation,” the investigators concluded. “Our study provides insights into the etiological basis [causes] for [fragile X].”