Local sequence context at KRAS codons modulates DNA repair efficiency: insights from molecular dynamics simulations

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Benzo[a]pyrene diol-epoxide (BPDE) induces DNA adducts, leading to mutagenesis, particularly at the KRAS gene's codon 12.
• The influence of tobacco smoke's genotoxic effects on DNA repair mechanisms is not fully understood.
• BPDE lesions may indicate individual DNA repair capacity and cancer risk.

Purpose of the Study:

• To model BPDE-adducted KRAS sequences at codons 12 and 14.
• To assess local helical distortion caused by BPDE adducts.
• To determine the impact of this distortion on nucleotide excision repair (NER).

Main Methods:

• Modeling of BPDE-adducted KRAS sequences at codons 12 and 14.
• Assessment of local helical DNA distortion.
• Evaluation of nucleotide excision repair (NER) efficiency and Rad4 binding.

Main Results:

• BPDE adducts at codon 12 cause distinct DNA distortions compared to codon 14.
• The distortion at codon 12 resembles canonical DNA structure, potentially evading repair.
• Impaired NER and compromised lesion recognition were observed at codon 12 due to altered Rad4 binding.

Conclusions:

• The mutational hotspot at KRAS codon 12 is linked to impaired NER.
• Local DNA sequence context critically influences repair efficiency.
• Findings offer insights into sequence-dependent DNA structure, repair, mutation accumulation, and cancer development.