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Scientists have uncovered a previously hidden role for a protein frequently mutated in cancer, showing that it helps maintain the stability of the genome at some of its most vulnerable sites.
The study sheds light on why the loss of this protein, called SMARCA4, can leave cells prone to accumulating genetic damage, which is associated with the development and progression of cancer.
By combining several cutting‑edge genomic approaches, the researchers were able to pinpoint not just where damage occurs, but also how the surrounding chromatin environment contributes to vulnerability or protection. Importantly, the findings indicate that it might one day be possible to exploit this weakness to treat cancer.
The study was led by scientists at The Institute of Cancer Research, London, and the findings were published in the journal Genome Biology. Funding for the work came from multiple sources, including the Medical Research Council, Cancer Research UK and The Institute of Cancer Research (ICR), which is both a research institute and a charity.
A key role for SMARCA4
SMARCA4 is a core component of a large protein complex known as SWI/SNF. This molecular machine helps organise DNA inside the cell nucleus so that genes can be switched on and off at the right time.
Mutations in SWI/SNF components are found in about one in five cancers, with SMARCA4 altered in close to 11 per cent of those cases. Despite this prominence, many of SMARCA4’s functions have not yet been uncovered. The new study adds an important piece to the puzzle by showing that SMARCA4 acts as a genomic ‘caretaker’ at unusual DNA structures known as G‑quadruplexes.
Although DNA is typically presented as a simple double helix, it can fold into a variety of shapes. Among these is the G‑quadruplex, or G4, which is a four‑stranded structure rich in guanine – one of the main four building blocks in DNA. These structures are common in the human genome and are often found in places where gene activity needs to be carefully regulated.
G‑quadruplexes can be useful. They can act as signposts, helping to control gene expression or recruit proteins needed for DNA replication and repair. However, they can also be hazardous. If a G‑quadruplex forms at the wrong time or persists for too long, it can block the cellular machinery that copies DNA, increasing the risk of breaks or mutations.
The researchers discovered that SMARCA4 has a crucial role in limiting these errors. By studying human cells lacking SMARCA4, they found striking increases in two hallmarks of genome instability at predicted G‑quadruplex sites: DNA double‑strand breaks and small sequence changes known as single‑nucleotide variants.
A pattern also seen in patients
What makes the findings particularly compelling is that the same pattern appears not only in laboratory cell models but also in tissue samples from cancer patients. Tumours carrying SMARCA4 mutations showed a higher proportion of mutations within G‑quadruplex sequences themselves, rather than merely nearby. This suggests that the absence of SMARCA4 leaves these regions of the genome particularly exposed.
In addition, the team found that the proportion of mutations at G‑quadruplexes in SMARCA4‑mutant cancers was even greater than that seen in tumours with mutations in TP53, a gene long known as the ‘guardian of the genome’. This comparison highlights just how important SMARCA4 may be in protecting DNA integrity at these important sites.
Turning a weakness into an opportunity
The study also explored how SMARCA4‑deficient cells respond to drugs that stabilise G‑quadruplexes. One such compound, called pyridostatin, locks G‑quadruplex structures in place. In cells already lacking SMARCA4’s protective influence, this proved especially harmful.
When treated with pyridostatin, SMARCA4‑deficient cells struggled to recruit important DNA repair factors after replication. The researchers observed signs of increased single‑stranded DNA gaps – another indicator of replication stress and genomic instability. Together, these findings hint at why cancers with SMARCA4 mutations might be particularly sensitive to therapies that target G‑quadruplexes.
This has clear clinical implications. Several G‑quadruplex‑stabilising drugs are already being tested in early‑stage clinical trials. If further research confirms these results, patients whose tumours carry SMARCA4 mutations could be prime candidates for such treatments, either alone or in combination with other therapies.
Globally, the potential reach is significant. Based on current cancer statistics, hundreds of thousands of people worldwide each year may develop cancers with SMARCA4 mutations. The benefit could extend even further, as defects in other SWI/SNF subunits have also been linked to sensitivity to G‑quadruplex‑targeting drugs.
Opening new research paths
Beyond this therapeutic promise, the study raises wider questions about genome maintenance. SMARCA4 is only one part of the SWI/SNF complex, which contains multiple subunits with distinct roles. The research community must now determine whether and how other components of the complex help safeguard G‑quadruplexes.
For now, the immediate impact is a deeper understanding of how genome instability arises in certain cancers. In the longer term, the hope is that insights like these will help turn a fundamental weakness of cancer cells into a therapeutic advantage.
First author Dr Alison Harrod, a Postdoctoral Training Fellow in the Epigenetics and Genome Stability Group at the ICR, said:
“G‑quadruplexes are a bit like knots in a rope. They can be helpful if they’re tied and untied at the right moments, but if they’re left in place, they tend to create stress and damage.
“We expected to see some vulnerability at G‑quadruplexes, but it was striking that the breaks and mutations were sitting right in the G4 sequences – and that this was so clear in the patient data, which is much more genetically complex than any cell line.”
Senior author Professor Jessica Downs, Deputy Head of the Cell and Molecular Biology Division at the ICR, said:
“SMARCA4 mutations are very common in cancer, yet the impact of these mutations in the initiation and progression of the disease remains incompletely understood. This study uncovered an important new role of SMARCA4, showing that a protein that organises packaging of DNA within the cell also acts as a protective factor at unusually folded DNA structures.
“The distinctive pattern of genetic changes we identified has the potential to significantly influence cancer progression in patients lacking SMARCA4 and helps us to understand the consequence of SMARCA4 loss in cancer more deeply.”
Image credit: congerdesign from Pixabay (modified)
