Critical roles of tyrosyl-DNA phosphodiesterases in cell tolerance to carnosol-induced DNA damage

Area of Science:

• Molecular Biology
• Cancer Research
• DNA Repair Mechanisms

Background:

• Carnosol exhibits anti-cancer properties, but its precise mechanism of action is not fully understood.
• Investigating the molecular pathways underlying carnosol's anti-carcinogenic effects is essential for therapeutic development.

Purpose of the Study:

• To elucidate the DNA damage and repair mechanisms targeted by carnosol in lymphoblastoid TK6 cell lines.
• To determine the role of tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2) in carnosol-induced DNA damage.

Main Methods:

• Utilized lymphoblastoid TK6 cell lines, including wild-type (WT) and TDP1/TDP2 deficient variants (TDP1-/- and TDP2-/-).
• Assessed DNA damage by quantifying DNA double-strand breaks (DSBs), γ-H2AX foci, and chromosomal aberrations (CAs).
• Investigated the formation of topoisomerase 1-DNA cleavage complexes (TOP1cc) and topoisomerase 2-DNA cleavage complexes (TOP2cc).

Main Results:

• Carnosol was demonstrated to induce DNA double-strand breaks (DSBs) in TK6 cells.
• Cells deficient in TDP1 or TDP2 exhibited supersensitivity to carnosol, with increased DNA damage accumulation (γ-H2AX foci and CAs).
• Carnosol treatment led to the formation of TOP1-DNA cleavage complexes (TOP1cc) and TOP2-DNA cleavage complexes (TOP2cc).

Conclusions:

• Carnosol induces DNA lesions associated with abnormal topoisomerase activity.
• TDP1 and TDP2 play significant roles in repairing carnosol-induced DNA damage, highlighting their importance in carnosol's anti-cancer effects.
• These findings provide critical insights into the molecular mechanisms underlying carnosol's anti-carcinogenic potential.