Hidden DNA shapes reveal a new vulnerability in cancer cells

SciLifeLab Group Leader Nasim Sabouri at Umeå University has published a new study in Nature Communications on a previously underexplored feature of the genome.

DNA is often depicted as a stable double helix, an elegant structure that carries our genetic information. Inside living cells, however, DNA is far more dynamic. It can twist and fold into alternative shapes that form only briefly, yet may have important biological consequences. One such shape is the i-motif, a four-stranded DNA structure that forms in regions rich in cytosine, one of DNA’s four building blocks.

“For a long time, i-motifs were thought to be too fragile to exist in living cells,” says Nasim Sabouri, SciLifeLab Group Leader at Umeå University. “What we show is that they do exist, but only very briefly, at a precise moment just before DNA is copied.”

For years, this belief was reinforced by laboratory experiments suggesting that i-motifs were only stable under acidic conditions, making it difficult to assess whether they formed inside cells at all.

Building on this, the study shows that i-motifs form at a specific point in the cell cycle and must be resolved before DNA replication can proceed. The researchers identified the protein PCBP1 as a key regulator of this process. If i-motifs are not removed in time, they can obstruct the DNA replication machinery, leading to genomic instability and defects in cell-cycle progression, processes closely linked to cancer development.

The work was conducted by a SciLifeLab-affiliated research group at Umeå University, combining molecular biophysics, computational modeling, and cell biology. Ongoing research now focuses on identifying the cellular conditions that favor i-motif formation and on assessing whether these transient DNA structures could be exploited as therapeutic targets in cancer.

Not all i-motifs are the same

A central conclusion of the study is that i-motifs are not uniform in their properties. Although they share a common structural core, their stability and biological behavior vary depending on their DNA sequence. The researchers found that i-motif stability depends on the number of cytosine–cytosine interactions that hold the structure together: the more interactions present, the more difficult it is for PCBP1 to unfold the structure.

Some i-motifs are further stabilized by an additional fold, known as a hairpin, within the same DNA sequence. Together, these elements form particularly resistant composite structures. To manage this diversity, cells rely on PCBP1 as a specialized factor that resolves i-motifs with structure-specific timing and efficiency. At the molecular level, PCBP1 first engages with flexible regions of the i-motif before progressively unfolding the structure. This process is essential for genome stability, as even brief delays in resolution can interfere with DNA replication.

Why this matters for cancer research

By showing that PCBP1 is required to clear i-motifs before DNA replication, the study identifies a potential vulnerability in cancer cells. Cancer cells often experience high levels of replication stress due to rapid and uncontrolled proliferation. Interfering with i-motif formation or resolution could exacerbate this stress and push cancer cells beyond a tolerable threshold, while leaving normal cells less affected.

These findings highlight an emerging therapeutic landscape that extends beyond the classical double helix, focusing instead on transient DNA structures and the proteins that regulate them.

What comes next

Having established that i-motifs influence a critical decision point in the cell cycle, the commitment to DNA replication, the next step is to identify the signals that govern their formation and resolution. The long-term goal is to determine whether these transient DNA structures can be harnessed as controllable elements for improved cancer diagnostics and for the development of more precise, targeted therapies.

DOI: 10.1038/s41467-026-68822-5

Main photo, from left to right: Nasim Sabouri, Pallabi Sengupta and Ikenna Obi. Photo taken by Rebecca Forsberg.