Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• APOBEC1 (A1) enzymes are cytidine deaminases primarily involved in RNA editing.
• Some A1 enzymes exhibit activity on single-stranded DNA (ssDNA).
• Human APOBEC3A (A3A) and APOBEC3B (A3B) enzymes introduce somatic mutations into nuclear DNA, contributing to cancer genomes.

Purpose of the Study:

• To investigate the mutagenic potential of A1 cytidine deaminases on chromosomal DNA.
• To explore the ssDNA substrate specificity of various mammalian A1 enzymes.
• To characterize the nuclear DNA mutator phenotype of mouse A1.

Main Methods:

• Molecular cloning and expression of various A1 enzymes.
• Assessing ssDNA substrate specificity.
• Analyzing mutation introduction in nuclear DNA and 5-methylcytidine deamination.
• Evaluating the formation of double-stranded DNA breaks.

Main Results:

• Cow, pig, dog, rabbit, and mouse A1 enzymes show intracellular ssDNA substrate specificity.
• Mouse A1 uniquely introduces somatic mutations into nuclear DNA with a 5'TpC context and deaminates 5-methylcytidine substituted DNA.
• Mouse A1 activity does not induce double-stranded DNA breaks, indicating an attenuated mutator phenotype similar to human A3B.

Conclusions:

• Mouse APOBEC1 is a source of somatic mutations in the mouse genome, potentially promoting oncogenesis.
• APOBEC1 may substitute for the lack of A3A and A3B-like enzymes in rodents, albeit with lower mutagenic activity.
• This challenges the notion that only APOBEC3 and AID enzymes are endogenous mutator enzymes in mammalian genomes.