Defining APOBEC-induced mutation signatures and modifying activities in yeast
Tony M Mertz1, Zachary W Kockler2, Margo Coxon3
1Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont, Burlington, VT, United States.
Methods in Enzymology
|April 18, 2025
Summary
This study introduces yeast-based methods to analyze APOBEC cytidine deaminases, crucial enzymes linked to cancer genome mutations. These validated techniques identify APOBEC mutation signatures and pathways, aiding cancer research.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- APOBEC cytidine deaminases protect against viruses but are implicated in cancer genome mutations.
- Human APOBEC3A and APOBEC3B are linked to specific COSMIC single base substitution (SBS) signatures in tumors.
Purpose of the Study:
- To present validated yeast-based methods for studying APOBEC cytidine deaminases.
- To determine APOBEC mutation signatures, genetic interactors, and chromosomal preferences.
- To assess APOBECs' role in cancer genome evolution and host defense.
Main Methods:
- Expression of human APOBEC3A and APOBEC3B in yeast.
- Experimental derivation of APOBEC-induced substitution patterns in dividing cells.
- High-throughput screening in yeast to investigate mutation-influencing pathways.
Main Results:
- Established yeast as a model to derive APOBEC mutation signatures, linking them to COSMIC SBS 2 and 13.
- Demonstrated the utility of yeast for high-throughput screening of APOBEC activity.
- Validated methods to study APOBEC genetic interactors and substrate preferences.
Conclusions:
- Yeast-based methods provide a scalable system to study APOBEC functions in cancer and viral restriction.
- These methods can assess the oncogenic potential of various APOBECs and orthologs.
- Understanding protective pathways against APOBEC activity is crucial for genome integrity.
