Strand-resolved mutagenicity of DNA damage and repair

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• DNA base damage is a primary driver of mutations that lead to cancer.
• Lesion segregation can create distinct mutation patterns and multiallelic variation.
• Strand-asymmetric processes like replication and transcription influence DNA damage and repair dynamics.

Purpose of the Study:

• To investigate how strand-asymmetric processes shape DNA damage and repair.
• To quantify genome-wide repair efficiency at single-base resolution.
• To identify genomic conditions that promote oncogenic mutagenesis.

Main Methods:

• Exploiting strand-phased mutation patterns and multiallelic variation caused by DNA damage.
• Comparing fidelity and damage tolerance across leading and lagging replication strands.
• Quantifying repair efficiency by analyzing mutations at persistent lesion sites.
• Assessing the impact of DNA accessibility versus damage gradients on mutation patterns.
• Investigating the role of nucleotide excision repair fidelity in specific genomic contexts.

Main Results:

• Replication strands exhibit identical fidelity and damage tolerance for small alkylation adducts, suggesting a shared translesion polymerase recruitment.
• This contrasts with strand-asymmetric tolerance observed for bulky UV-induced adducts.
• DNA accessibility significantly influences repair efficiency, more so than DNA damage gradients.
• Specific genomic conditions were identified that actively corrupt nucleotide excision repair, driving oncogenic mutagenesis.

Conclusions:

• Strand-asymmetric mechanisms are fundamental to the formation, tolerance, and repair of DNA damage.
• DNA accessibility is a key determinant of mutation patterns genome-wide.
• Understanding these processes provides insights into cancer genome evolution and potential therapeutic targets.