DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• APOBEC3 (A3) enzymes are mutagens causing genetic alterations.
• A3 activity leads to 'mutation showers' near DNA breakpoints.
• Mechanisms for most A3-induced mutations remain unclear.

Purpose of the Study:

• Classify diverse patterns of clustered mutagenesis in tumor genomes.
• Identify novel A3 mutation patterns and their underlying mechanisms.
• Investigate the role of DNA mismatch repair in A3 mutagenesis.

Main Methods:

• Analysis of clustered mutagenesis patterns in tumor genomes.
• Classification of A3-associated mutation patterns.
• Investigating the association between A3 activity and DNA mismatch repair.

Main Results:

• A new A3 mutation pattern, nonrecurrent diffuse hypermutation (omikli), was identified.
• Omikli occurs independently of focal hypermutation (kataegis).
• Omikli is associated with DNA mismatch repair activity, contributing significantly to genome-wide A3 mutations.

Conclusions:

• DNA mismatch repair provides single-stranded DNA for A3 activity.
• Omikli preferentially targets gene-rich, early-replicating domains.
• A3 mutagenesis, via mismatch repair, generates potent, impactful mutations, exceeding other carcinogens.