Collateral mutagenesis funnels multiple sources of DNA damage into a ubiquitous mutational signature

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• Mutations arise from DNA damage, replication errors, and repair processes.
• Human genomes exhibit distinct mutation signatures across cell types.
• The single base substitution signature SBS5 is uniquely prevalent across tissues and cell types, including neurons and germlines.

Purpose of the Study:

• To investigate the unknown etiology of the ubiquitous SBS5 mutation signature.
• To model the processes underlying mutation generation to understand SBS5 origins.
• To determine if DNA damage and repair mechanisms contribute to the SBS5 signature.

Main Methods:

• Computational modeling of mutation generation processes.
• Analysis of mutation signatures in cancerous and non-cancerous human cells.
• Correlation analysis of SBS5 rates with DNA damage and repair signatures across the genome.

Main Results:

• Modeling suggests SBS5 results from DNA synthesis errors triggered by various DNA damages.
• SBS5 rates positively correlate with signatures of endogenous and exogenous DNA damage.
• SBS5 mutation rates co-vary with genomic repair rates, aligning with model predictions.
• Evidence indicates SBS5 arises from both translesion synthesis and DNA repair pathways.

Conclusions:

• The SBS5 signature is a "funnel" output, where diverse DNA damages converge to a common mutation spectrum.
• SBS5 reflects the occasional, shared utilization of a DNA polymerase during translesion synthesis and DNA repair.
• Understanding SBS5 provides insights into fundamental DNA maintenance and error-prone processes across human cells.