Genome instability can lead to various diseases, but cells have robust mechanisms to repair DNA damage. Recently, researchers have uncovered new insights into how cells respond to DNA damage.
During cell division, the risk of genetic material damage is high. Cells must copy their entire genetic material, which involves replicating billions of genetic letters. This process often results in “reading errors” within the genome. Additionally, other factors contribute to the accumulation of DNA damage throughout a person’s lifetime, including exposure to sunlight, alcohol, and smoking, all of which can harm genetic material and potentially lead to cancer.
Cells are not defenseless against such damage; they possess a wide array of mechanisms to respond to DNA damage. This response is formally known as the DNA damage response (DDR), where specific signaling pathways kick in to promptly recognize and repair DNA damage, helping maintain the cell’s viability.
A fresh perspective on the DNA damage response
A research team at Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, has closely examined one of these signaling pathways. They discovered a new mechanism in the DNA damage response that involves an RNA transcript. Their findings expand our understanding of the DNA damage response and connect it more intimately with RNA metabolism.
Dr. Kaspar Burger, who leads a junior research group in the Department of Biochemistry and Molecular Biology, spearheaded this study, and the results have been published in the journal Genes & Development.
RNA transcripts as stabilizers of the genome
“In our research, we concentrated on long non-coding RNA transcripts. Previous studies indicate that certain transcripts may act as regulators of genome stability,” explains Kaspar Burger. The investigation centered on the nuclear enriched abundant transcript 1, or NEAT1, which is present in high levels in numerous tumor cells. NEAT1 is known to respond to DNA damage and cellular stress, yet its precise role in the DNA damage response was not understood.
“Our hypothesis was that RNA metabolism involves NEAT1 in the DNA damage response to help ensure genome stability,” Burger states. To test this, the team conducted experiments to see how NEAT1 responds to severe genomic damage, specifically DNA double-strand breaks, in human bone cancer cells. They found that “DNA double-strand breaks increase both the levels of NEAT1 transcripts and the amount of N6-methyladenosine marks on NEAT1,” according to the researcher.
RNA modification marks often misregulated in cancer cells
The methyladenosine marks on RNA transcripts are a relatively new area of study. They belong to epitranscriptomics, a biological field focused on how RNA modifications influence gene expression. Methyl groups play a critical role in this process, and it is known that RNA modifications can be disrupted in cancer cells.
NEAT1 activates a DNA repair factor
Kasper Burger and his team’s experiments show that an uptick in DNA double-strand breaks leads to heightened methylation of NEAT1, causing alterations in its secondary structure. This results in an accumulation of highly methylated NEAT1 at various DNA lesions, facilitating the recognition of damaged DNA. Conversely, reducing NEAT1 levels experimentally delayed the DNA damage response and increased DNA damage.
Although NEAT1 does not directly repair DNA damage, the Würzburg researchers found that it plays a crucial role in the controlled release and activation of an RNA-binding DNA repair factor. This mechanism allows cells to detect and repair DNA damage more effectively.
The researchers believe that understanding the function of NEAT1 methylation in the recognition and repair of DNA damage could lead to new treatment strategies for tumors with high NEAT1 expression. However, further research is needed to see if these findings can be applied to complex tumor models derived from simpler cell systems.
Dr. Kaspar Burger’s research received support from the German Cancer Aid and the Mildred Scheel Early Career Center for Cancer Research (MSNZ) in Würzburg.
During cell division, the risk of damaging genetic material is significant as cells must replicate their entire genetic code, which includes billions of base pairs. This task can lead to repeated “reading errors” within the genome. Additionally, factors like sunlight, alcohol, and smoking also contribute to the buildup of DNA damage over time, which can lead to cancer and other diseases.
Fortunately, cells have a variety of mechanisms to respond to such DNA damage. The term for this response is the DNA damage response (DDR), which ensures that specific pathways activate to quickly recognize and repair DNA damage, thus promoting cell survival.
A fresh perspective on the DNA damage response
A research team from Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, closely examined one of these signaling pathways and discovered a new role for RNA transcripts in the DNA damage response. Their findings enhance our understanding of this process and its connection to RNA metabolism.
Dr. Kaspar Burger, a junior research group leader in the Department of Biochemistry and Molecular Biology, led this study, and the results have been published in the journal Genes & Development.
RNA transcripts as stabilizers of the genome
“In our research, we focused on long non-coding RNA transcripts, with prior findings suggesting that some may regulate genome stability,” Kaspar Burger explains. The study examined nuclear enriched abundant transcript 1 or NEAT1, which appears in high levels in many tumor cells. It’s known to respond to DNA damage and cellular stress, but its specific role in the DNA damage response was not well-defined.
“Our hypothesis was that NEAT1 plays a part in RNA metabolism related to the DNA damage response to maintain genome stability,” states Burger. To verify this, the research team explored how NEAT1 responded to severe genomic damage—specifically, DNA double-strand breaks—in human bone cancer cells. Their investigation revealed that “DNA double-strand breaks trigger an increase in both the quantity of NEAT1 transcripts and the N6-methyladenosine marks on NEAT1,” according to the scientist.
RNA modification marks often misregulated in cancer cells
Methyladenosine modifications on RNA transcripts have only recently come under scientific scrutiny. They fall under the realm of epitranscriptomics, which investigates how RNA modifications influence gene expression. In this process, methyl groups play an important role, and it is noted that RNA modifications are often mislocated in cancer cells.
NEAT1 activates a DNA repair factor
The experiments led by Kaspar Burger and his team demonstrated that frequent DNA double-strand breaks lead to excessive methylation of NEAT1, resulting in changes to its secondary structure. Consequently, heavily methylated NEAT1 accumulates at certain damage sites to assist in recognizing broken DNA. When NEAT1 levels were artificially reduced, the cells showed a delayed DNA damage response, correlating with higher levels of DNA damage.
While NEAT1 itself does not repair DNA damage directly, the research team in Würzburg found that it facilitates the controlled release and activation of an RNA-binding DNA repair factor, enabling cells to efficiently identify and repair DNA damage.
The researchers believe that further understanding of NEAT1’s methylation role in recognizing and fixing DNA damage may lead to new treatment avenues for tumors with elevated NEAT1 expression. However, further studies are required to determine if these results, obtained from simple cell systems, can be extended to more complex tumor models.
Support for Kaspar Burger’s research was provided by the German Cancer Aid and the Mildred Scheel Early Career Center for Cancer Research (MSNZ) in Würzburg.
