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APOBEC-1 cofactors regulate APOBEC3-induced mutations in hepatitis B virus
Zhigang Chen1, Thomas L Eggerman1,2, Alexander V Bocharov1
1Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Journal of Virology
|January 27, 2025
Summary
APOBEC3 proteins (A3s) are crucial for immunity and cancer. This study reveals that APOBEC-1 (A1) cofactors and hnRNPs regulate A3 mutational activity, impacting viral defense and cancer mutations.
Area of Science:
- * Molecular biology
- * Virology
- * Cancer genetics
Background:
- * APOBEC3 (A3) proteins are key host factors in innate immunity against viruses and in driving cancer mutations.
- * The regulatory mechanisms governing A3 protein activity and the variability in A3-induced mutations remain largely unexplored.
- * A3s function in complexes, and their family member APOBEC-1 (A1) requires cofactors for activity, suggesting a similar regulatory pathway for A3s.
Purpose of the Study:
- * To investigate the role of A1 cofactors and associated heterogeneous nuclear ribonucleoproteins (hnRNPs) in regulating A3 mutational activity.
- * To elucidate how these factors influence A3s' interaction with DNA substrates and their mutational efficiency.
- * To understand the differential impact of A3 regulation on viral genomes versus human cancer mutations.
Main Methods:
- * Utilized hepatitis B virus (HBV) cellular replication as a model system to study A3 activity.
- * Employed co-expression and gene knockdown (siRNA) strategies to assess the impact of A1 cofactors and hnRNPs.
- * Performed mutagenesis on A3G and A3B to disrupt protein interactions with hnRNPs.
- * Conducted HBV genome-wide mutation analyses to evaluate A3C accessibility and mutational efficiency.
Main Results:
- * A1 cofactors and hnRNPs were found to be involved in regulating A3 mutational activity, with effects varying based on A3 association strength (A3C > A3G > A3B).
- * Co-expression of A1 cofactors significantly increased A3 mutational activity, while knockdown decreased it.
- * Disruption of A3-hnRNP interactions via mutagenesis substantially reduced A3 mutational activity.
- * A1 cofactors enhanced A3C accessibility to HBV DNA and promoted kataegis-like hypermutations.
Conclusions:
- * A1 cofactors and hnRNPs are essential regulators of A3 mutational activity, interacting closely with A3 proteins.
- * These cellular factors play a significant role in modulating A3-induced mutations under physiological conditions.
- * Understanding A3-associated factor interactions offers potential therapeutic targets for controlling A3-driven mutations in cancer.
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