Every time we step outside, our cells are exposed to ultraviolet (UV) radiation, which is known to cause deoxyribonucleic acid (DNA) damage. While our bodies have built-in repair mechanisms to undo mutations in the DNA, scientists are still unraveling the intricate ways our genome responds to such damage.
In a recent study published in Nature Communications, Turkish researchers investigated how UV radiation reshapes the three-dimensional (3D) organization of the genome and its impact on gene activity.
They found that UV exposure alters genome folding, potentially influencing DNA repair efficiency and cellular responses. By mapping these changes over time, this study provided new insights into how cells maintain genomic stability, with implications for cancer research and skin care.
Study: UV-induced reorganization of 3D genome mediates DNA damage response. Image Credit: Nor Gal/Shutterstock.com
Radiation and DNA damage
UV radiation is a persistent environmental stressor, well known for damaging DNA and increasing cancer risk. When UV rays strike cellular DNA, they create lesions such as pyrimidine-pyrimidone adducts and cyclobutane pyrimidine dimers, which disrupt normal genetic processes.
Cells rely on nucleotide excision repair to correct this damage, but the efficiency of this mechanism varies across the genome.
Previous studies have largely focused on how ionizing radiation affects DNA organization, showing that damage can reorganize chromatin structure and impact DNA repair efficiency. However, little is known about how UV radiation specifically alters the 3D genome landscape.
Researchers suspect that genome folding may influence how efficiently the damage is recognized and repaired, particularly in genes that regulate stress responses.
By examining the immediate effects of UV radiation on chromatin architecture, this study aimed to bridge this knowledge gap and uncover new aspects of the DNA damage response.
The Current Study
To investigate how UV exposure influences the 3D structure of the genome, the researchers conducted a series of experiments using human cells. They exposed HeLa-S3 cells to UV radiation (254 nm, 20 J/m²) and collected samples at three key time points: 12 minutes, 30 minutes, and 60 minutes post-exposure.
Furthermore, to analyze changes in genome organization, they used high-resolution Hi-C sequencing, a powerful technique that maps chromatin interactions.
The researchers first examined how UV-induced DNA lesions affected genomic compartments, which are large-scale structural units that organize genes based on their activity levels. By comparing pre- and post-UV samples, they assessed shifts in chromatin compaction and transcriptional activity.
They also explored the role of topologically associating domains (TADs), which help regulate gene expression by structuring the genome into functional units. TAD boundary insulation and chromatin loop formation were key focal points in this study, as changes in these features could influence DNA repair efficiency.
Additionally, the researchers performed ribonucleic acid (RNA) sequencing to monitor gene expression changes. They analyzed repair efficiency at chromatin loops, looking at whether specific genome structures made certain regions more or less accessible for repair processes.
Furthermore, using a graph neural network approach, they identified genome segments undergoing major structural alterations after UV exposure. This comprehensive, multi-omics approach enabled the researchers to build a detailed map of how genome folding responds to UV-induced stress.
Major Findings
The study found that UV radiation significantly alters the 3D genome structure, leading to distinct changes in chromatin interactions and gene regulation. Specifically, the researchers observed that UV exposure increased short- to mid-range chromatin interactions while weakening long-range ones, suggesting a shift in genome compaction.
One key discovery was that TAD boundaries became more insulated after UV exposure. This strengthened insulation was particularly evident in regions associated with DNA repair and stress response genes, suggesting that these structural changes could enhance the cell’s ability to manage damage.
However, some areas of the genome also showed decreased accessibility, potentially slowing repair efficiency in certain regions.
Additionally, the study found that chromatin loops, which help regulate gene expression, were reorganized after UV exposure.
Loops that formed within 12 minutes of UV exposure were enriched with key DNA damage response genes, such as the proto-oncogenes JUN and FOS, which play crucial roles in cellular stress adaptation.
In contrast, after UV exposure, the loops that previously served as binding sites for repair-associated transcription factors disappeared, indicating a complex regulatory shift in response to damage.
A surprising finding was that genome segments with lower pre-UV regulatory activity gained new chromatin loops post-exposure, likely mediated by the CCCTC-binding factor (CTCF) protein. This suggested that UV-induced changes in genome topology may actively influence gene regulation rather than being a passive consequence of damage.
Conclusions
Overall, the study demonstrated that genome organization plays a critical role in the DNA damage response, and UV radiation reshapes the 3D genome, influencing DNA repair and gene activity.
By mapping these structural changes, researchers provided valuable insights into the mechanisms that maintain genomic stability.
These findings could have implications for improving cancer prevention and developing strategies to protect against UV-induced genetic damage.
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