Sequence-specific recognition of cancer drug-DNA adducts by HMGB1a repair protein

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Cisplatin (Cp) and oxaliplatin (Ox) are platinum-based chemotherapy drugs that exert their effects by forming covalent drug-DNA adducts.
• The efficacy of these drugs is influenced by the cellular recognition and repair of these adducts by proteins like High Mobility Group Box 1a (HMGB1a).
• Prior research indicates that HMGB1a exhibits varying binding affinities for Cp- and Ox-DNA adducts, depending on the specific drug and the surrounding DNA sequence.

Purpose of the Study:

• To investigate the relationship between DNA adduct deformation free energy and HMGB1a binding affinity.
• To elucidate the molecular mechanisms underlying the differential binding of HMGB1a to oxaliplatin-DNA adducts in specific sequence contexts.

Main Methods:

• Computational modeling to calculate the free energy of DNA deformation (bending and minor groove opening) upon drug adduct formation.
• Analysis of DNA sequence context effects on drug-DNA adduct deformability.

Main Results:

• HMGB1a's binding affinity for drug-DNA adducts is directly correlated with the free energy required to deform the DNA molecule.
• Oxaliplatin-DNA adducts in the TGGA sequence context exhibit significantly higher deformation free energy compared to cisplatin-DNA or oxaliplatin-DNA in other contexts.
• Steric hindrance from methyl groups on thymine bases in the Ox-TGGA context restricts minor groove opening and DNA bending, reducing HMGB1a binding.

Conclusions:

• The differential binding affinity of HMGB1a for platinum drug-DNA adducts is mechanistically linked to the energetic cost of DNA deformation.
• Sequence-dependent DNA structural changes, such as minor groove crowding, play a critical role in modulating protein recognition of drug-DNA adducts.
• Understanding these sequence-specific interactions can inform the development of more effective platinum-based cancer therapies.