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Cationic Porphyrin-Mediated G-Quadruplex DNA Oxidative Damage: Regulated by the Initial Interplay between DNA and
Wenqin Zhou1,2,3, Yu Cheng2, Bo Song4
1Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian 116024, China.
Abstract:
G-quadruplex (G4) ligand-induced DNA damage has been involved in many physiological functions of cells. Herein, cationic porphyrin (TMPyP4)-mediated DNA oxidation damage was investigated aiming at mitochondrial G4 DNA (mt9438) and its structural analogue of the thrombin-binding aptamer (TBA). TMPyP4 is found to stabilize TBA G4 but destabilize mt9438. For two resulting DNA-TMPyP4 assemblies, the distinct light-induced singlet oxygen (1O2) generation and the subsequent DNA damage were found. For mt9438-TMPyP4, a slower 1O2-induced DNA damage takes place and results in the formation of DNA aggregation. In contrast, 1O2 tends to promote DNA unfolding in a relatively faster rate for TBA-TMPyP4. Despite of such distinct DNA damage behavior, UV resonance Raman spectra reveal that for both mt9438-TMPyP4 and TBA-TMPyP4 the DNA damage commonly stems from the guanine-specific oxidation. Our results clearly indicate that the ligand-mediated DNA damage is strongly dependent on the initial interplay between DNA and the ligand.
Insights
Cationic porphyrin (TMPyP4) causes distinct DNA damage to mitochondrial G4 DNA and thrombin-binding aptamer G4. The ligand-DNA interaction dictates the type of damage, impacting cellular functions.
Area of Science:
- Biochemistry
- Molecular Biology
- Photochemistry
Background:
- G-quadruplex (G4) DNA structures are crucial in various cellular processes.
- Ligand-induced G4 DNA damage plays a role in cellular functions.
- Cationic porphyrins are known to interact with G4 DNA.
Purpose of the Study:
- To investigate cationic porphyrin (TMPyP4)-mediated DNA oxidation damage.
- To compare the damage mechanisms on mitochondrial G4 DNA (mt9438) and thrombin-binding aptamer (TBA).
- To understand how initial DNA-ligand interactions influence G4 DNA damage outcomes.
Main Methods:
- Investigated TMPyP4 interaction with mt9438 and TBA G4 DNA.
- Analyzed light-induced singlet oxygen generation and subsequent DNA damage.
- Utilized UV resonance Raman spectroscopy to identify damage mechanisms.
Main Results:
- TMPyP4 stabilized TBA G4 but destabilized mt9438 G4.
- Distinct light-induced singlet oxygen generation and DNA damage observed for both complexes.
- mt9438-TMPyP4 showed slower, aggregation-inducing damage, while TBA-TMPyP4 exhibited faster DNA unfolding.
- DNA damage in both cases originated from guanine-specific oxidation.
Conclusions:
- The initial interplay between G4 DNA and ligands significantly dictates the resulting DNA damage.
- Ligand-mediated G4 DNA damage is highly sequence and structure-dependent.
- Understanding these interactions is key to developing targeted therapies.
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