Acute expression of human APOBEC3B in mice results in RNA editing and lethality

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• RNA editing contributes to genetic heterogeneity and diseases like cancer.
• The cytosine deaminase APOBEC3B is linked to tumor evolution via DNA mutation.
• APOBEC3B's potential role in RNA editing remained uninvestigated.

Purpose of the Study:

• To engineer a mouse model for studying human APOBEC3B overexpression.
• To investigate APOBEC3B's impact on tissue homeostasis.
• To determine if APOBEC3B functions as a C-to-U RNA editing enzyme.

Main Methods:

• Developed a novel doxycycline-inducible mouse model for human APOBEC3B.
• Administered sustained high levels of APOBEC3B to mice.
• Conducted RNA-sequencing on mouse tissues with high APOBEC3B expression.

Main Results:

• APOBEC3B overexpression led to rapid cellular fitness decline, organ dysfunction, and lethality.
• Identified frequent UCC-to-UUC RNA editing events in APOBEC3B-expressing tissues.
• Observed RNA editing events distinct from genomic DNA alterations.

Conclusions:

• This study demonstrates a novel deaminase-dependent RNA editing function for APOBEC3B.
• Established a preclinical tool for investigating APOBEC3B's role in carcinogenesis.
• Highlights APOBEC3B as a potential driver of cancer development through RNA editing.