Competition for DNA binding between the genome protector replication protein A and the genome modifying APOBEC3...

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• The human APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family comprises eleven cytosine deaminases.
• These enzymes modify cytosine to uracil on RNA and single-stranded DNA (ssDNA) substrates.
• This modification is crucial for lipid metabolism, antibody gene evolution in adaptive immunity, and viral genome inactivation in innate immunity.

Purpose of the Study:

• To discuss the interplay between APOBEC enzymes, replication protein A (RPA), and their roles in cancer evolution.
• To highlight how APOBEC3 subfamily members can induce mutations in genomic DNA.
• To explain the mechanism of APOBEC-mediated mutagenesis despite RPA's protective role.

Main Methods:

• Review of existing literature on APOBEC enzymes, RPA, and DNA repair pathways.
• Analysis of mutation patterns in cancer genomes indicative of APOBEC activity.
• Discussion of the competition between APOBEC enzymes and RPA for ssDNA binding.

Main Results:

• APOBEC3 enzymes (excluding E) can cause off-target deaminations on genomic ssDNA, leading to uracil formation.
• Uracil is promutagenic and can lead to mutations if not repaired by uracil DNA glycosylase (UNG).
• APOBEC enzymes compete with RPA for ssDNA access; some APOBECs can displace RPA and are overexpressed in tumors.
• Despite RPA presence, cancer genomes exhibit mutation biases suggesting APOBEC activity.

Conclusions:

• APOBEC3 enzymes are implicated in cancer evolution through their mutagenic activity on genomic DNA.
• The balance between APOBEC activity, RPA binding, and DNA repair mechanisms influences mutation outcomes.
• Understanding this interplay is crucial for deciphering cancer mutational landscapes and developing targeted therapies.