Genetic modifiers of APOBEC-induced mutagenesis

Area of Science:

• Genetics
• Cancer Biology
• Molecular Biology

Background:

• APOBEC3A and APOBEC3B (A3B) are key mutagens in human cancer genomes.
• Understanding genetic modulators of APOBEC-induced mutagenesis is crucial for cancer research.

Approach:

• A large-scale screen in yeast identified 61 gene deletions that enhance A3B-induced mutations.
• Epistasis analysis with UNG1 loss distinguished between error-free bypass and deamination suppression mechanisms.
• Mutation spectra analysis revealed genotype-specific patterns of single-stranded DNA (ssDNA) formation and nucleotide incorporation.

Key Points:

• Identified three multifactorial signatures of APOBEC-induced mutations: H3K56 acetylation failure, CTF18-RFC complex defects, and HR-mediated lesion bypass defects.
• BRCA1/2-deficient breast cancers exhibit significantly higher APOBEC-induced mutations (3-4 fold).
• In BRCA1/2-deficient tumors, Rev1-mediated C-to-G substitutions drive increased APOBEC mutations on the lagging strand during replication.

Conclusions:

• Discovered key factors influencing DNA replication dynamics and APOBEC mutation abundance during tumor progression.
• Elucidated a novel role for BRCA1/2 in HR-dependent bypass of APOBEC-induced lesions during cancer cell replication.