HKU and SZBL Scientists Discover the First Human DNA-Cutting Enzyme That Senses Physical Tension, Marking a Breakthrough in Understanding How Cells Prevent Genetic Disorders

An international research team has identified a human protein, ANKLE1, as the first DNA-cutting enzyme (nuclease) found in mammals that can detect and respond to physical tension in DNA. This ‘tension-sensing’ mechanism is crucial for maintaining the integrity of our genetic material during cell division—a process that, when disrupted, can lead to cancer and other serious diseases.

The study, published in Nature Communications, represents a major leap forward in our understanding of how cells protect their DNA. It is the result of a cross-disciplinary collaboration between Professor Gary Ying Wai CHAN’s laboratory at the School of Biological Sciences, The University of Hong Kong (HKU) and Dr Artem EFREMOV’s biophysics team at Shenzhen Bay Laboratory (SZBL), with additional contributions from researchers at the Hong Kong University of Science and Technology and the Francis Crick Institute in London. 

DNA under stress: the hidden danger during cell division

Every time a cell divides, it must carefully copy and separate its DNA. But this process sometimes goes awry, leaving the DNA entangled and forming ‘chromatin bridges’—threads of DNA that stretch between the two new cells as they try to separate. These bridges are placed under significant physical tension as the division machinery pulls the cells apart. If these bridges break in an uncontrolled manner, they can cause serious genetic errors that may lead to cancer or immune diseases.

‘Think of these chromatin bridges as tightropes under tension during cell division,’ explains Professor Gary Chan, senior author of the study. ‘If they snap suddenly, it can wreak havoc on the genome, causing mutations and instability.’ Until now, scientists have not fully understood how cells safely resolve these tense DNA bridges without triggering catastrophic damage.

ANKLE1: the genome’s first ‘tension-sensing’ DNA cutter

The new research reveals that ANKLE1, a protein previously linked to DNA repair, acts as a specialised ‘tension sensor’ nuclease during cell division. Using advanced single-molecule experiments—where individual DNA molecules are manipulated with tiny magnetic tweezers—the team discovered that ANKLE1 can ‘feel’ when DNA is stretched or twisted. Remarkably, ANKLE1 only cuts DNA under tension or when DNA is supercoiled (twisted), as occurs in overstretched chromatin bridges. This precision prevents the DNA from breaking randomly, which could otherwise lead to genetic chaos.

‘Our discovery shows that ANKLE1 acts like a smart pair of scissors,’ says Dr Artem Efremov, co-senior author and biophysics expert. ‘It only cuts DNA when it is really needed—when the DNA is stretched and at risk of breaking in a harmful way. This is a completely new way for cells to sense and respond to mechanical stress on their genetic material.’

Traditional biological techniques were combined with cutting-edge biophysical tools, allowing the team to apply precise forces to DNA molecules and observe ANKLE1’s activity in real time. ‘This project could only have succeeded by bringing together expertise from both disciplines,’ notes Professor Chan. ‘By using physics-based approaches, we could see how ANKLE1 responds to the physical state of DNA, something that is invisible with standard biological methods.’

Implications for genome stability and cancer therapy

This discovery marks a significant step forward in understanding how cells maintain the stability of their genetic material under physical stress. By revealing how ANKLE1 acts as a tension-sensing DNA cutter, the research provides crucial insights into how cells prevent dangerous DNA breaks that can lead to cancer and other diseases. Intriguingly, the study suggests that inhibiting ANKLE1 could push cancer cells—already prone to genome instability—past a tipping point, potentially making them more vulnerable to existing treatments. As a result, ANKLE1 may represent a novel target for cancer therapy, opening new strategies for exploiting the vulnerabilities of tumour cells while deepening our understanding of genome maintenance.

The full paper, titled ‘ANKLE1 processes chromatin bridges by cleaving mechanically stressed DNA’ is available at https://www.nature.com/articles/s41467-025-65905-7

For more about Professor Gary Ying Wai Chan’s work: https://sites.google.com/site/garychanlab

For more about Dr Artem Efremov’s work:  https://artemefremovlab.com