Scientists at the Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, have discovered how a gene-regulating protein forms tiny liquid-like droplets inside the cell nucleus (the compartment that stores and manages DNA) to guard against cancer.

Their study, published in Nature Communications, shows that these protein droplets act as control centres that keep tumour-suppressor genes switched on.

Guarding the genome

Our genetic material is tightly packed inside the cell nucleus, wrapped around proteins called histones.

To keep the right genes active, cells rely on proteins like CHD1, which reorganise this DNA structure when needed.

The Kanazawa team led by Katsuya Sakai, discovered that CHD1 uses a flexible region to form tiny liquid-like droplets, called condensates, that act as hubs for controlling the activity of crucial cancer-guarding genes.

These condensates help bring together DNA, RNA, and regulatory proteins to keep tumour-suppressor genes functioning properly.

When protection fails

Normally, CHD1 condensates act as hubs that guard tumour-suppressor genes.

But this protective system can break down.

A cancer-associated mutation known as E1321fs deletes part of CHD1’s structure that is essential for forming condensates.

Without these droplets, CHD1 cannot properly regulate key tumour-suppressor genes, including TP53 and CDKN1B.

As a result, cells carrying this mutation lose an important layer of defence and become more vulnerable to uncontrolled growth and cancer development.

Experimental approach

To investigate this mechanism, the researchers combined state-of-the-art imaging and molecular biology tools:

• High-speed atomic force microscopy (HS-AFM): captured how CHD1 proteins interact with DNA and assemble into condensates at the nanoscale.
• Droplet assays: tested how CHD1 forms condensates in the presence of DNA, RNA, and nucleosomes.
• Confocal microscopy: visualised condensate formation in living cells, comparing normal CHD1 with the mutant form.
• CRISPR-Cas9 genome editing: engineered human cells carrying the E1321fs mutation to track its impact on tumour-suppressor genes.
• Mouse experiments: showed that restoring the missing part of CHD1 reactivated condensate formation and reduced tumour growth.

Together, these experiments revealed how condensate failure leads directly to a breakdown in cancer protection.

A molecular network for cancer protection

The team also mapped how CHD1 droplets interact with other molecules.

They found that the condensates attract RNAs and epigenetic regulators such as the MLL complex, another system often disrupted in cancers.

This suggests that CHD1 droplets serve as molecular gathering points to coordinate multiple layers of tumour suppression.

Author’s comment

“Our findings reveal a new way in which cells guard themselves against cancer,” says Sakai.

“By showing how this protein organises DNA into droplets that keep tumour-suppressor genes active, we hope to open up new possibilities for cancer therapies that target condensate dynamics.”

Future perspectives

While this study establishes that condensate failure can drive cancer, several questions remain.

The team notes that it is still unclear which sequences within CHD1 drive condensation and how condensate size and concentration are regulated inside living cells.

Future research

• Explore the biophysical rules controlling condensate formation in the crowded environment of the nucleus.
• Investigate whether restoring condensate dynamics could provide a new therapeutic strategy for cancers carrying CHD1 mutations.
• Examine how CHD1 works together with other condensate-forming proteins to maintain genome integrity.

Article: Condensation-dependent interactome of a chromatin remodeler underlies tumor suppressor activities

Source: Nano Life Science Institute (NanoLSI), Kanazawa University