The research focuses on blocking the activity of PCNA (Proliferating Cell Nuclear Antigen), a protein essential for DNA replication and repair, by identifying molecules capable of impairing its function inside cancer cells.

‘We are working on finding molecules that, once inside cancer cells, will act like a Trojan horse. We expect their action to disrupt the DNA replication mechanism, meaning that cells in which such molecules are present will be unable to divide. Simply put, we are trying to eliminate selected activities of the PCNA protein, without which cell division is impossible', explains Wojciech Strzałka, PhD, from the Faculty of Biochemistry, Biophysics and Biotechnology at Jagiellonian University.

PCNA plays a central role in the cell cycle, forming a ring structure of three molecules that binds to DNA and facilitates the recruitment of enzymes responsible for synthesising new genetic material. Researchers say disrupting this mechanism could prevent cancer cells, which divide rapidly, from replicating DNA and repairing damage.

‘The lack of a functional PCNA ring prevents proper DNA duplication in the cell and its effective repair. This means that a cell with such dysfunction can be put in a state of replication stress, which can ultimately lead to its death’, says Arkadiusz Borek, PhD, co-author of the invention.

The team has identified a single-stranded DNA molecule that binds more strongly to PCNA than natural DNA, effectively blocking the protein’s interaction with the DNA helix and preventing replication at an earlier stage than previously targeted approaches.

Researchers say the strategy differs from existing methods, which focus on disrupting interactions between PCNA and other proteins involved in DNA copying and repair.

‘The solution we propose has the potential to find practical applications, as the molecules could be delivered directly to cancer cells using advanced and existing drug carriers. This way, we can reduce the risk that a cell division inhibitor will disrupt the division of healthy cells in patients. In addition, I imagine that, if successful, further preclinical research will enable the development of molecules with improved parameters that will effectively block PCNA activity in cells', says Monika Bzowska, PhD, professor at the university’s Department of Cell Biochemistry.

Blocking PCNA activity could also increase cancer cells’ sensitivity to DNA-damaging chemotherapy drugs, including etoposide, doxorubicin and cisplatin, which are often less effective when tumour cells retain the ability to repair DNA damage.

The team has developed a test to track the binding of a fluorescence-labelled DNA aptamer to PCNA, enabling the identification of compounds that block the protein’s interaction with DNA. The university’s CITTRU is seeking partners to advance the research and increase the technological readiness of potential therapies.

Further research and preclinical testing will be required before the approach can be considered for clinical application. (PAP)

PAP - Science in Poland

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