Cells inherit protection from one of the sun’s overlooked harms—UV-damaged RNA. Although the harms of UV-damaged RNA aren’t as well recognized as the harms of UV-damaged DNA, they shouldn’t be dismissed. UV-damaged RNA contributes to RNA-protein and RNA-RNA crosslinks that disturb RNA processing and protein synthesis—likely with deleterious health effects.

Fortunately, as scientists at the Max Planck Institute (MPI) of Immunobiology and Epigenetics have discovered, UV-damaged RNA can be sequestered by stress granules. These granules, which are formed by a dsRNA helicase called DHX9, are passed on to daughter cells along with UV-damaged RNA. Ordinarily, DHX9 remains in the nucleus unless the cell is exposed to UV radiation, which may explain why DHX9 stress granules have not been observed in mother cells.

Additional details appear in Cell, in an article titled, “RNA damage compartmentalization by DHX9 stress granules.” These details include the development of an experimental method called fluorescence-activated nonmembrane condensates isolation (FANCI). It utilizes flow cytometry sorting of fixed and sonicated cell lysates to purify stress granules (SGs).

“Our FANCI technology revealed that DHX9 SGs are enriched in damaged intron RNA, in contrast to classical SGs that are composed of mature mRNA,” the authors of the Cell article wrote. “UV exposure causes RNA crosslinking damage, impedes intron splicing and decay, and triggers DHX9 SGs within daughter cells.”

The article’s senior author, Asifa Akhtar, PhD, is a group leader and director at the MPI of Immunobiology and Epigenetics. She recalled that she was astonished when her team found that DHX9 can form droplets outside the nucleus. She said that it was “finding a giant snowball in the desert.”

The formation of extranuclear DHX9 droplets was not the only surprise for the scientists. Initially, the scientists suspected that the DHX9 granules act as a defense mechanism against DNA damage. “Contrary to this hypothesis, we found that DHX9 granules were not triggered by various forms of DNA damage stimuli,” said Yilong Zhou, PhD, the study’s first author and a researcher in Akhtar’s laboratory. “This prompted us to dig into the real trigger.”

With their FANCI technique, the researchers found that the DHX9 stress granules were packed with damaged RNA. “The damaging effect of UV light on RNA is frequently underestimated, overshadowed by its impact on DNA,” Akhtar noted. “Now, we discovered an elegant mechanism by which cells can segregate and neutralize harmful UV-damaged RNA with the help of DHX9 granules.”

“DHX9 SGs promote cell survival and induce dsRNA-related immune response and translation shutdown, differentiating them from classical SGs that assemble downstream of translation arrest,” the authors of the Cell article indicated. “DHX9 modulates dsRNA abundance in the DHX9 SGs and promotes cell viability.”

When cells detect RNA damage induced by UV exposure, they rapidly trap the damaged molecules into DHX9 granules, thereby preventing them from causing further harm. This safeguarding mechanism effectively confines the damage and ensures that it doesn’t spread uncontrollably within the cell causing further chaos.

“What fascinated us even more was the observation that cells with DHX9 granules always appeared in pairs,” Zhou related. “[This indicates] that the granules are not formed in the original UV-damaged mother cell but later on in the newly born daughter cells.”

The hypothesis was confirmed by live cell video imaging. “You can literally see that DHX9 normally resides in the nucleus,” Zhou pointed out. “But shortly after cell division, when the two daughter cells have formed, it gathers into droplets in the cytoplasm.”

This immunofluorescence micrograph of HeLa cells shows that after UV-induced RNA damage, the proteins DHX9 (green) and G3BP1 (red) form stress granules in the cytoplasm. DHX9 is also found in the nucleus (cell nuclei are displayed in blue). [MPI of Immunobiology and Epigenetics, Akhtar]
Interestingly, preventing DHX9 granule formation in daughter cells leads to severe cell death, highlighting the ability of daughter cells to spot and stash away their progenitors’ damaged RNA into DHX9 granules. “This process is like wiping the slate clean, preparing [cells of the new generation] to begin their own journeys without dragging along the baggage from the previous generation,” Akhtar observed.

Understanding how our daughter cells defend themselves against UV-induced parental RNA damage not only deepens our understanding of the cell cycle but also opens up new possibilities for medical research. Conditions such as sunburn, neurodegenerative disorders, and cancer are intricately tied to disruptions in RNA balance and irregularities in the cell cycle.

Akhtar concluded that “a better understanding of how a newly generated cell selectively recognizes and degrades damaged RNA could lead to new therapeutic targets for diseases characterized by RNA mismanagement or dysregulation of the stress response.”

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