APOBEC3 Enzymes in Genome Instability and Cancer

A link between dysregulation of DNA damage and repair systems has been implicated in tumorigenesis and etiology of many cancers.

Matthew D. Weitzman, PhD, and a team from the Center for Childhood Cancer Research are investigating a role for a family of human enzymes in generating mutations in DNA that could contribute to cancer initiation or drug resistance. They previously demonstrated that the human apolipoprotein-B mRNA-editing catalytic polypeptide-like 3 (APOBEC3) family of cytidine deaminases exerts potent antiviral activity against a range of human DNA viruses. However, additional studies revealed that the APOBEC3 enzymes can also act on the host genome, creating mutations, activating DNA damage signaling pathways, and producing genome instability that may lead to transformation of normal human cells.

Studies are currently underway to determine mechanisms that regulate the mutator activity of APOBEC3 enzymes, with the goal of understanding how dysregulation generates clusters of DNA mutations that destabilize the genome. Ultimately, the hope is to be able to exploit this vulnerability with targeted therapies for human cancers that aberrantly express APOBEC3 enzymes.