ANKLE1 senses mechanical tension in DNA and helps resolve DNA bridges connecting separating daughter nuclei. ANKLE1 (green) localises to the midbody (red) during cell division. In cells lacking ANKLE1, DNA bridges become elongated and remain unresolved. Using magnetic tweezers, applying tension to DNA induces cleavage by ANKLE1, demonstrating its tension-dependent DNA cutting activity. Image adapted from Jiang et al, Nature Communications (2025).
An international research team has identified a human protein, ANKLE1, as the first DNA-cutting enzyme (nuclease) in mammals capable of detecting and responding to physical tension in DNA. This ‘tension-sensing’ mechanism plays a vital role in maintaining genetic integrity 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 advance in the understanding of cellular DNA protection. The research was conducted through 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 (HKUST) and the Francis Crick Institute in London.
DNA under stress: the hidden danger during cell division
Every time a cell divides, it must accurately replicate and segregate its DNA. However, this process can sometimes go wrong, leaving DNA entangled and forming ‘chromatin bridges’—threads of genetic material that stretch between the two new cells as they try to separate. These bridges break under the mechanical tension generated as cells pull apart, potentially causing severe genetic errors linked to cancer and immune disorders.
‘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 research reveals that ANKLE1, a protein previously associated with DNA repair, functions 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 cause 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.’
The team combined traditional biological techniques with cutting-edge biophysical tools, applying controlled forces to DNA molecules while observing 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 safeguard genetic material under physical stress. By revealing how ANKLE1’s role as a tension-sensitive 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—beyond a critical threshold, potentially making them more susceptible to existing treatments. As a result, ANKLE1 may emerge as a novel therapeutic target, offering new strategies to exploit tumour vulnerabilities while deepening the knowledge 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
由香港大學（港大）領導的國際團隊取得突破性發現，首次在哺乳動物中發現及證實一種名為ANKLE1 的人類蛋白質，能夠感應並回應DNA物理張力的DNA切割酶（核酸酶）。這種「張力感應」機制在細胞分裂過程中維持遺傳物質完整性至關重要；該機制失常可能導致癌症等嚴重疾病。 這項研究結果已經發表在《自然-通訊（Nature Communications）》， 象徵着科學家在理解細胞保護自身 DNA 機制方面的重大進展。研究由港大生物科學學院陳英偉教授團隊與深圳灣實驗室（Shenzhen Bay Laboratory, SZBL）Artem Efremov 博士團隊跨領域合作完成；並獲香港科技大學及倫敦弗朗西斯·克里克研究所（Francis Crick Institute in London）的科學家參與。
DNA 承受壓力：細胞分裂過程中的隱藏危機
每當細胞分裂時，DNA 都要被精準複製並平均分配到兩個新細胞。然而，此過程並非每次都能順利進行——有時DNA 會纏結，形成「染色質橋」——這些 DNA 絲狀結構在細胞分裂過程中連接着兩個新細胞，並承受着強烈的物理張力。若這些橋梁以不受控制的方式斷裂，便可能引發嚴重的基因錯誤，導致癌症或免疫疾病。
研究通訊作者陳英偉教授解釋： 「可以 細胞分裂時出現的染色質橋想像成被拉緊的繩索。如果它們突然斷裂，便會對基因組造成嚴重損害，導致突變和不穩定。」在此之前，科學家尚未完全了解細胞如何能在不造成災難性損害的情況下，安全解決這些承受張力的DNA橋。
ANKLE1：基因組首個「張力感應」DNA切割酶
研究揭示，原本已知與DNA 修復相關的蛋白質ANKLE1，其實在細胞分裂過程中扮演着一種具「張力感應」的核酸酶。研究團隊運用先進的單分子實驗技術——以微型磁鉗操控單條 DNA 分子——發現ANKLE1 能夠「感受」DNA的拉伸或扭曲，並只會切割處於張力或超螺旋（扭曲）狀態的DNA，就如同被過度拉緊的染色質橋一樣。這種精確性機制防止了DNA隨機斷裂，維持基因組穩定。
共同通訊作者、生物物理學專家Efremov博士表示：「我們的研究顯示，ANKLE1就像一 智能剪刀，只會在必要時——當 DNA 受拉伸、處於危險之際才會進行切割。這是一種細胞感應並回應基因物理壓力的全新機制。」
團隊結合傳統生物學與尖端生物物理技術，對DNA分子施加精確力量，並實時觀察ANKLE1的活性。陳英偉教授補充說：「這項研究的成功，全賴多學科專業的結合。通過物理學的方法，我們得以觀察ANKLE1 如何回應DNA的物理狀態，這是傳統生物學手段難以捕捉的現象。」
基因組穩定性與癌症治療新啟示
該發現大幅推進對細胞在物理張力下維持遺傳物質穩定性的理解。研究揭示ANKLE1作為張力感應型DNA 切割酶的角色，為細胞如何防止危險的DNA斷裂、從而避免癌症和其他疾病提供了關鍵線索。
研究亦指出，抑制 ANKLE1 可能令基因組不穩定的癌細胞進一步失衡，因此抑制 ANKLE1 可能會讓癌細胞更容易被現有的化療藥物殺死。ANKLE1 有望成為癌症治療的新靶點，為利用腫瘤細胞弱點帶來新策略，同時加深對基因組維護機制的理解。
有關研究可參考以下網址：https://www.nature.com/articles/s41467-025-65905-7
關於陳英偉教授和Artem Efremov博士的研究工作和他們的研究團隊：