PICH acts like a lookout, spotting and attaching to tiny DNA threads called ultrafine anaphase bridges (UFBs). When PICH is inactivated (knockdown, KD), more of these threads form and break, leading to dangerous DNA rearrangements that can be identified by whole genome sequencing. The blue lines in the circular diagrams indicate sites of genomic rearrangements, often involving interchromosomal fusions—a hallmark of tumourigenesis that drives cancer development. Image adapted from Kong et al, Nucleic Acids Research (2024)
香港大學（港大）的研究人員發現細胞在分裂過程中保護DNA的重要機制，為對抗癌症等疾病提供了新的見解。這項研究由港大理學院生物科學學院陳英偉教授和李嘉誠醫學院病理學系馬海騰教授領導，揭示了一種名為PICH的蛋白質，在防止可能導致癌症等疾病的遺傳錯誤中所扮演的重要角色。相關研究成果已刊登於國際學術期刊《Nucleic Acids Research》。

Researchers at The University of Hong Kong (HKU) have made an exciting discovery about how human cells protect DNA during cell division, offering new insights into combating diseases such as cancer.

Led by Professor Gary Ying Wai CHAN from the School of Biological Sciences, Faculty of Science, and Professor Ken Hoi Tang MA from the Department of Pathology, LKS Faculty of Medicine, the research uncovers the vital role of a protein called PICH in preventing genetic errors that can lead to diseases such as cancer. Their findings were recently published in the journal Nucleic Acids Research.

Ultrafine Anaphase Bridges – A Hidden Threat to Our Genome
Every time a cell divides, it must ensure that its DNA is accurately copied and split between the two new cells. However, tiny threads of DNA, known as ultrafine anaphase bridges (UFBs), can sometimes form and cause problems if not properly managed. These UFBs can be thought of as invisible enemies that tangle up our genetic material.

Through their research, the HKU team discovered that the protein PICH acts like a radar, detecting these UFBs and helping to resolve them. They found that when PICH is missing or not functioning properly, cells experience severe genetic damage, including broken DNA, the formation of small DNA-containing structures called micronuclei, and activation of the cell’s emergency response systems, which ultimately leads to cell death. Moreover, their findings revealed that such damage can trigger rearrangements of chromosomes—hallmarks of cancer.

PICH prevents dangerous rearrangements of DNA
Building on these findings, the team further investigated the role of PICH in maintaining genetic stability. They found that without PICH, cells not only suffer from severe DNA damage but also accumulate significant genetic errors. A mutated version of PICH that cannot recruit other helper proteins provides only partial protection, while a completely inactive version of PICH fails to resolve UFBs, resulting in even more extensive genetic damage. PICH’s activity is crucial for breaking down these DNA threads and preventing genetic chaos. Notably, when PICH is missing, genetic errors are more likely to occur in non-centromeric regions of the DNA due to the breakage of UFBs, leading to dangerous chromosome rearrangements that can cause disease.

Their research proposes that PICH protects human DNA through two key mechanisms. First, it assists another protein, topoisomerase IIα (TOP2A), in untangling the DNA threads. Second, it works with a protein called BLM helicase to convert tangled threads into a simpler, more manageable form. Together, these two actions ensure that DNA threads are properly resolved, preventing genetic errors that could lead to cancer.

“Our research shows how vital PICH is in protecting our DNA from damage during cell division. By understanding how PICH works, we can explore new ways to treat cancers such as colorectal, gastric and breast cancer, which are strongly linked to a high degree of chromosomal instability,” said Professor Gary Ying Wai Chan, one of the corresponding authors of the paper.

“Next-generation sequencing (NGS) is a powerful tool for detecting genomic instability in diseases such as cancer. In our research, we used NGS to identify mutations in cells lacking PICH, demonstrating its effectiveness in uncovering genetic errors. This productive collaboration with Professor Chan has highlighted the importance of teamwork in scientific research,” added Professor Ken Hoi Tang Ma, another corresponding author of the study.

This study highlights the critical role of PICH in maintaining the integrity of human genetic material. Understanding how PICH works opens new possibilities for developing treatments for diseases caused by genetic instability, such as cancer. “By targeting pathways involving PICH, we may be able to develop new therapies to prevent or treat these conditions,” explained Professor Gary Ying Wai Chan.

The findings are detailed in the paper ‘The Interplay of the Translocase Activity and Protein Recruitment Function of PICH in Ultrafine Anaphase Bridge Resolution and Genomic Stability’, published in the journal Nucleic Acids Research.

The full paper can be accessed at https://doi.org/10.1093/nar/gkae1249

For more information about the research teams, please visit their respective websites:
Professor Gary Ying Wai Chan: https://sites.google.com/site/garychanlab/
Professor Ken Hoi Tang Ma: https://bit.ly/4jc7Gft

超細後期橋——基因組的隱形敵人
每當細胞分裂時，必須確保DNA被準確地複製並分配到兩個新細胞中。然而，在細胞分裂過程中，偶爾會形成一些稱為超細後期橋（ultrafine anaphase bridges，UFBs）的微小DNA絲狀結構。這些UFBs就像糾纏遺傳物質的隱形敵人，如果未能妥善處理，會引發一系列問題。

港大的研究團隊發現，蛋白質PICH就像雷達一樣，能檢測並協助處理這些UFBs。研究顯示，當PICH缺失或無法正常運作時，細胞會遭受嚴重的遺傳損傷，例如DNA斷裂、形成微核等結構，並啟動細胞的緊急應對系統，最終導致細胞死亡。此外，研究還揭示這種損傷可能引發染色體重排——這正是癌症的典型特徵之一。

PICH 防止DNA發生重排的危險
基於這些發現，研究團隊進一步探討了PICH在維持遺傳穩定性中的關鍵作用。他們發現，在沒有PICH時，細胞不僅會遭受顯著的DNA損傷，還會累積大量的遺傳錯誤。一個無法招募輔助蛋白的突變型PICH只能在一定程度上減輕遺傳損傷，但無法完全恢復細胞的穩定性；而一個完全失活的PICH則完全無法處理UFBs導致的問題，引發更嚴重的遺傳損傷。由此可見，PICH的活性對於分解這些DNA絲狀結構並防止遺傳混亂至關重要；特別是當PICH缺失時，UFBs的斷裂更容易在非著絲粒區域引發遺傳錯誤，最終導致染色體重排，從而引發嚴重疾病。

研究人員提出，PICH 通過兩種方式保護我們的 DNA。首先，它協助另一種蛋白質——拓撲異構酶 IIα（TOP2A）——解開 DNA絲狀結構。其次，它與名為 BLM 解旋酶的蛋白質合作，將這些糾纏的絲狀結構轉換成較容易處理的形式。這種雙重作用確保 DNA絲狀結構能被妥善處理，從而防止可能導致癌症的遺傳錯誤。

「我們的研究顯示了PICH在細胞分裂過程中保護DNA免受損傷的重要性。通過了解PICH的工作機制，我們可以探索新的方法來治療與高染色體不穩定性相關的癌症，如結直腸癌、胃癌和乳腺癌。」論文的通訊作者之一陳英偉教授解釋道。

「次世代基因定序（Next-generation sequencing，NGS）是一種強大的工具，用於檢測癌症等疾病中的基因組不穩定性。在我們的研究中，我們使用NGS來識別缺乏PICH的細胞中的突變，展示了其在揭示遺傳錯誤方面的有效性。與陳教授的這次富有成果的合作強調了團隊合作在科學研究中的重要性。」研究的另一位通訊作者馬海騰教授補充道。

這項研究強調了PICH在維持遺傳物質完整性方面的關鍵作用。深入了解PICH的工作機制，為開發治療由遺傳不穩定性引起的疾病（如癌症）提供了新的可能性。「通過針對涉及PICH的通路，讓我們有望設計出新的療法，用於預防或治療這些疾病。」陳英偉教授說。

以上研究以The Interplay of the Translocase Activity and Protein Recruitment Function of PICH in Ultrafine Anaphase Bridge Resolution and Genomic Stability為題，已正式發表在國際知名期刊《Nucleic Acids Research》。

如欲參閱完整論文，可透過以下連結瀏覽：https://doi.org/10.1093/nar/gkae1249

參看更多關於陳英偉教授和馬海騰教授的研究工作：
https://sites.google.com/site/garychanlab/
https://bit.ly/4jc7Gft