The Chromatin Bridge-Cutting Scissor Enzyme, Unveiled by Biologists, Prevents DNA Damage and Autoimmunity.

A research team led by Dr Gary Ying Wai Chan of the University of Hong Kong (HKU) School of Biological Sciences has revealed the function of a unique enzyme, ANKLE1. ANKLE1 acts on chromatin bridges confined to the centrosome of dividing cells. By cutting these bridges, ANKLE1 prevents damage to genetic material and prevents the immune system from mistakenly attacking the body’s own cells.

Understanding the mechanism by which chromatin bridges are cleaved during cell division is important for developing new strategies to prevent or treat diseases such as cancer and autoinflammatory disorders. The research was recently published in advanced science.

During cell division, the DNA must be properly divided into two new cells. However, errors can occur during this process, causing pieces of DNA to stick together and form structures called chromatin bridges. These bridges are like strings of DNA that connect two separate blocks of chromosomes in the new cell. As a result, they will inevitably fall into the middle of the cell division process.

When chromatin bridges are trapped in the centrosome, they will be broken by contractile forces mediated by the actin-myosin complex, which can lead to DNA damage and the formation of small nuclei called “micronuclei”, causing genome instability, which is a characteristic of many solids. . Tumors and activation of innate immune responses that contribute to autoinflammation.

To investigate the alternative mechanism used by cells to dissolve chromatin bridges, the research team recently discovered that ANKLE1, a unique endonuclease (enzyme), plays a critical role in cleavage of chromatin bridges midstream during cell division, thus avoiding catastrophic breakage induced by mechanolysis. forces. This alternative mechanism helps ensure proper segregation and stability of DNA, which is important for the prevention of diseases such as cancer and autoinflammatory disorders.

Role of ANKLE1 in preventing DNA damage and autoimmunity

Previously, scientists identified an endonuclease called LEM-3 in Caenorhabditis elegans, a microscopic roundworm commonly used as a model organism in biological research. LEM-3 has been found to play a role in resolving chromatin bridges in the ‘midbody’, a structure that connects two daughter cells during cell division. The middle of the body is finally cut off, a process known as cleavage, which results in the complete separation of the two cells.

To understand the cellular functions of ANKLE1, which is the human equivalent of LEM-3, the research team used the CRISPR/Cas9 genome-editing technology to delete the ANKLE1 gene in human cells. The team found that loss of ANKLE1 leads to increased formation of extended chromatin bridges, suggesting that cleavage of the bridges by ANKLE1 prevents further DNA stretching. In the absence of ANKLE1, persistent bridges would eventually be broken by the contractile forces of actomyosin separating the two daughter cells. This mechanical breakage results in massive DNA fragmentation, resulting in the formation of micronuclei and released DNA in cytosolic DNA, which can trigger immune responses and lead to inflammation.

Importantly, loss of ANKLE1 leads not only to DNA damage and genome instability, but also to strong activation of cGAS-STING innate immunity. The cGAS-STING pathway is a major innate immune defense system against pathogens by sensing DNA present in the cytosol. In the absence of ANKLE1, fragments of DNA are readily generated when the bridge is broken, and the cytosolic DNA is erroneously thought to be pathogenic DNA. These results indicate that ANKLE1 plays roles in maintaining genome stability and preventing autoimmunity.

research importance

The research not only yields a key discovery of a mechanism that uses a body-tethered endonuclease (ANKLE1) as a ‘scissor’ to cut chromatin bridges to prevent genome instability, but also advances our understanding of the link between chromatin bridges and innate immune responses.

“More and more research data indicates that immune responses play important roles in determining the clinical outcome of many conventional anticancer drugs,” said Dr. Gary Ying Wai Chan. “For example, the use of antitumor drugs is a common strategy for the treatment of solid tumors. However, whether stimulation of immune responses due to the resulting chromatin bridges is partially responsible for the antitumor effect remains unclear. The relationship between chromosomal instability and innate immunity will certainly be an area of ​​research. Cancer holds enormous promise for breakthroughs.”