Research team identifies a new DNA protection mechanism

DNA strands. Credit: Case Western Reserve University

Researchers from Case Western Reserve University have identified a new mechanism by which a protein known to repair damaged DNA protects DNA integrity by maintaining its structural shape.

The discovery, which includes the 53BP1 protein, provides insight into understanding how cells maintain DNA integrity in the nucleus, which is critical to preventing diseases such as premature aging and cancer.

The study was conducted by a research team led by Youwei Zhang, associate professor of pharmacology at Case Western Reserve School of Medicine and a member of the Molecular Oncology Program at Case Comprehensive Cancer Center. The results were published on January 18, 2022 in Nature Communications.

DNA, or deoxyribonucleic acid, is the chemical name for the molecule that carries genetic instructions in all living things.

The large protein 53BP1 is known for its ability to determine how cells repair a particular type of DNA damage – DNA double strand break (DSB), in which the two strands of DNA are broken together, leaving a free end of DNA floating in the cell nucleus.

When DSB occurs, if not repaired, the DNA ends can fuse with what they should not under normal conditions, potentially disrupting genetic information. In the short term, cells with untreated DNA may kill themselves, but if the cell loses this self-monitoring, it may begin the journey toward cancer.


In this study, the team discovered that 53BP1 has a biological function in mediating the structure of DNA, specifically in a highly compact region called heterochromatin.

The researchers found that this new function involves a new form of 53BP1 activity, in which the protein accumulates in regions of condensed DNA and forms tiny liquid droplets — a process called liquid-liquid phase separation, similar to mixing oil with water for a salad dressing. .

The team determined how 53BP1 can form liquid droplets: they find that this process requires the participation of other proteins known to support the structure of highly condensed DNA. But they, in turn, discovered that 53BP1 actually stabilized the assembly of these proteins in these DNA regions, which is important for maintaining overall DNA function.

They then performed a detailed molecular analysis to break the large protein into small pieces and identify pieces important for 53BP1’s liquid droplet formation. They also altered the amino acids of a specific locus of the 53BP1 protein and identified the contribution of several amino acids that are critical to this new function.

“Most excitingly, through these comprehensive analyzes, we found that this novel protective activity of 53BP1 is independent of the widely known role of this protein in DNA damage repair, suggesting an entirely new function of 53BP1,” Zhang said. “Our study indicates that in addition to modulating DSB repair, 53BP1 contributes to maintaining genome stability through the formation of these fluid droplets.”

With this new information, Zhang and his team hope to better understand how to prevent diseases like cancer, and even design treatments that use this new feature of 53BP1 to treat cancers in the future.

Zhang’s lab focuses on understanding cell biology to develop anticancer therapies — specifically how cells protect DNA stability. Without this protection, DNA can cause genome instability and eventually lead to the early onset of degenerative disorders such as premature aging and cancer.

Zhang said, “Our goal is to understand the molecular mechanisms that maintain genome stability in human cells by identifying the genes and signaling pathways involved. In the long term, we hope to translate this knowledge into potential cancer treatment strategies.”

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more information:
Lei Zhang et al, 53BP1 regulates heterochromatin through liquid phase separation, Nature Communications (2022). DOI: 10.1038 / s41467-022-28019-y

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