Discovery Led by Researchers from Szeged Could Pave the Way for Novel Cancer Therapies

Scientists from the Hungarian Centre of Excellence for Molecular Medicine (HCEMM), the HUN-REN Biological Research Centre, Szeged, and the University of Szeged, working together with foreign experts, have presented their results in a recent paper published in Nucleic Acids Research, one of the world's leading journals in molecular biology. The study shows that K63-linked ubiquitylation of S2P-RNAPII regulates transcription in a DNA-PK-dependent manner in response to DNA double-strand breaks.

The human genome (the complete DNA content of cells) is constantly exposed to various stressors. Preserving genome integrity is vital, if errors accumulate in the DNA, it can lead to cellular disfunction, tumor formation, or cell death. To prevent this, cells rely on multiple DNA repair pathways. DNA double-strand breaks (DSBs) are among the most harmful forms of DNA damage, and DNA-PK is a central factor in the cellular response to them, particularly through non-homologous end joining (NHEJ).

Repair is especially important at regions of the genome where transcription takes place. This is the process where the cell uses one strand of the DNA double helix as a template to produce RNA - essentially copying the information stored in the DNA into RNA. These RNAs then produce proteins, or fulfil regulatory, structural, or repair-related functions within the cell. In protein-coding genes, this transcription is primarily carried out by the RNA polymerase II (RNAPII) enzyme, which moves along the gene and assembles the RNA strand in sequence.

Under normal conditions, RNAPII continuously performs the transcription required for gene expression. However, if one of the most severe types of damage - double-strand break - occurs, the cell must rapidly halt transcription in the affected region. Failure to do so can lead to the production of faulty RNA molecules and compromise genome stability, potentially contributing to the development of cancer. When DNA lesions persist or prove difficult to repair, RNAPII must be removed from the damaged sites to allow repair to proceed.

According to the study, the DNA-dependent protein kinase (DNA-PK) enzyme plays an important role in sensing and repairing DNA double-strand breaks. The authors demonstrated that activity of this enzyme is required for RNAPII to receive the signal to temporarily halt transcription. Using a range of molecular and cell biology approaches, the researchers demonstrated that when DNA-PK function is inhibited, cells are less capable of responding properly to DNA damage.

Interrupting transcription is a logical step for the organism: if the "text" (genetic information) to be copied is damaged, it is not a good idea to continue copying and distributing it.

The authors also point out that transcription and DNA repair are far more closely linked than previously thought. RNAPII is not merely a passive victim of DNA damage (meaning it does not just encounter an obstacle and stop transcribing when damage occurs), but an active participant in the cellular response that helps preserve genome stability. The process described in the study acts as a molecular switch, determining when the cell should pause transcription and when it should initiate repair processes.

The significance of the discovery extends beyond basic research. The study provides important new insight into how cells coordinate gene expression and genome protection mechanisms under stress. Failure in DNA repair are known to contribute to a wide range of diseases, particularly cancer. A better understanding of the processes that link transcription and DNA repair could support the development of new therapeutic strategies. For example, inhibiting DNA repair can sensitise tumour cells to radiotherapy or DNA-damaging chemotherapy, thereby increasing the chances of recovery.