PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Protein arginine methyltransferase 5 (PRMT5) is frequently overexpressed in various cancers, making it a significant therapeutic target.
• PRMT5 plays an essential role in normal physiological processes, posing a challenge for targeted therapies due to potential dose-limiting toxicities.
• Combinatorial therapeutic approaches are needed to overcome PRMT5 dependency in cancer treatment.

Purpose of the Study:

• To investigate the role of PRMT5 in DNA repair mechanisms.
• To explore the impact of PRMT5 inhibition on cancer cell viability and DNA damage.
• To evaluate the synergistic potential of PRMT5 and PARP inhibitors in cancer therapy.

Main Methods:

• PRMT5 depletion and inhibition were employed to study its effects on DNA repair.
• Homologous recombination (HR) DNA repair assays were performed.
• RNA splicing patterns, specifically of TIP60/KAT5, were analyzed.
• The synergistic effects of PRMT5 and PARP inhibitors were assessed in acute myeloid leukemia cells.

Main Results:

• PRMT5 depletion or inhibition significantly impairs homologous recombination (HR) DNA repair.
• This impairment leads to DNA damage accumulation, p53 activation, cell-cycle arrest, and cell death.
• PRMT5 inhibition causes aberrant splicing of TIP60/KAT5, selectively affecting its lysine acetyltransferase activity and compromising HR.
• Combined inhibition of PRMT5 and PARP demonstrates synergistic effects on acute myeloid leukemia cells.

Conclusions:

• PRMT5 is a critical regulator of HR DNA repair through its influence on TIP60/KAT5 splicing.
• Targeting PRMT5 can induce synthetic lethality in cancer cells by impairing DNA repair.
• The combination of PRMT5 and PARP inhibitors presents a promising synergistic therapeutic strategy for acute myeloid leukemia and potentially other cancers.