Scientists Discover First Human DNA-Cutting Enzyme That Responds to Tension

An international team of researchers has identified ANKLE1 as the first known human nuclease (a DNA-cutting enzyme) that can detect and respond to physical tension in DNA. 

This unique “tension-sensing” capability plays a key role in protecting the genome during cell division, a process where even small errors can lead to cancer or other serious diseases.

Published in Nature Communications, the study marks a major advance in our understanding of how cells maintain genetic stability.

DNA Under Stress: The Hidden Danger During Cell Division

Every time a cell divides, it must replicate and evenly split its DNA between the two new cells.

But this process isn’t always smooth. Sometimes, DNA becomes entangled, forming what's known as “chromatin bridges” - thin strands of genetic material stretched between dividing cells. These bridges are under mechanical tension, and when they snap, the resulting DNA damage can trigger genetic instability linked to cancer and immune-related disorders.

Think of these chromatin bridges as tightropes under tension during cell division. If they snap suddenly, it can wreak havoc on the genome, causing mutations and instability.

 Gary Chan, Professor and Study Senior Author, University of Hong Kong

Until now, scientists have lacked a clear understanding of how cells safely resolve these high-tension DNA structures.

ANKLE1: The Genome’s First ‘Tension-Sensing’ DNA Cutter

The study identifies ANKLE1, a protein previously associated with DNA repair, as a specialized tension-sensitive nuclease.

Through single-molecule experiments using magnetic tweezers, the team observed how ANKLE1 reacts to physical stress on DNA. They found that it only cuts DNA when it’s under tension or supercoiled, conditions that typically occur in overstretched chromatin bridges.

This selective activity is critical. By cutting only when DNA is at risk of breaking unpredictably, ANKLE1 helps prevent harmful genetic errors.

Our discovery shows that ANKLE1 acts like a smart pair of scissors. 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.

Dr. Artem Efremov, Study Co-Senior Author and Biophysics Expert, University of Hong Kong

The success of the project hinged on combining biology with physics.

This project could only have succeeded by bringing together expertise from both disciplines. 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.

Gary Chan, Professor and Study Senior Author, University of Hong Kong

Implications for Genome Stability and Cancer Therapy

This discovery sheds light on how cells protect their genome during the physically demanding process of division. By revealing ANKLE1’s role as a precision DNA cutter that senses mechanical stress, the study offers new insight into cellular defense systems that prevent harmful DNA breaks.

Importantly, the findings open up potential therapeutic avenues.

Since many cancer cells already exhibit high levels of DNA stress and instability, inhibiting ANKLE1 might push them past their breaking point - making them more vulnerable to existing treatments. This positions ANKLE1 as a promising target for future cancer therapies while expanding our understanding of genome maintenance mechanisms.