Mechanism behind DNA damage control discovered

Researchers at the University of Helsinki have identified a mechanism that is critical for the survival of cells under genotoxic stress.

New finding could help develop novel anti-cancer approaches to improve the cancer cell killing effects of chemotherapy, said a press release issued by the University of Helsinki.

DNA damage is occurring in our cells all the time due to external agents, such as exposure to sun, or internal agents, like reactive oxygen species. To detect and repair DNA lesions, cells have evolved DNA damage response. Activation of this response underpins genome integrity, which is crucial for preventing the onset of many human pathologies, including hematological disorders, neurodegenerative diseases, and cancer.

DNA damage elicits transient yet profound alterations in cellular gene expression programs. Previous work has established that cells need to shut down gene transcription by RNA polymerase II to facilitate DNA repair and limit the production of abnormal transcripts.

In a study that appeared online on 26 February in the prestigious journal Molecular Cell, researchers at the University of Helsinki have now added a new wrinkle to the story. The collaborative effort led by the Barborič laboratory has uncovered that activating gene transcription is equally important for how cells confront the genotoxic assault.

“As the results were coming in, the bigger picture began to emerge. We found how and why CDK9 gets activated upon genotoxic stress,” said Andrii Bugai, doctoral student in the laboratory and first author of the study, adding, “In the final analysis there are no alternatives: cells either induce gene transcription or they will die.”

“Because chemotherapeutic drugs can activate DNA damage response, the drug-induced cancer cell killing might be greatly enhanced when combined with specific pharmacological inhibitors of CDK9. This combinatorial approach or its derivatives could be an important way forward in our battle with cancer,” said Barborič.

The laboratory headed by Matjaž Barborič conducts research at the Faculty of Medicine, University of Helsinki. This study was supported, among others, by the Academy of Finland, the Sigrid Jusélius Foundation, and the University of Helsinki Doctoral Program in Biomedicine.