The spectrum of APOBEC3 activity: From anti-viral agents to anti-cancer opportunities

Abstract

The APOBEC3 family of cytosine deaminases are part of the innate immune response to viral infection, but also have the capacity to damage cellular DNA. Detection of mutational signatures consistent with APOBEC3 activity, together with elevated APOBEC3 expression in cancer cells, has raised the possibility that these enzymes contribute to oncogenesis. Genome deamination by APOBEC3 enzymes also elicits DNA damage response signaling and presents therapeutic vulnerabilities for cancer cells. Here, we discuss implications of APOBEC3 activity in cancer and the potential to exploit their mutagenic activity for targeted cancer therapies.

Keywords: APOBEC3; Cytosine deaminase; DNA damage response; Mutational patterns; Synthetic lethality.

Figure 1.. APOBEC3 enzymes are single-strand-specific DNA cytosine deaminases.

(A) The APOBEC3 gene cluster is located on chromosome 22. Green arrows depict single deaminase domain family members. Blue arrows depict double deaminase domain family members. (B) APOBEC3 enzymes deaminate cytosine resulting in a DNA uracil base. (C) Molecular outcomes of APOBEC3-mediated deamination events include low-fidelity replication of uracil resulting in mutations, processing of uracils resulting in ssDNA nicks or dsDNA breaks, and high-fidelity excision and repair with no resulting DNA lesion.

Figure 2.. APOBEC3 deamination at cellular ssDNA templates activates DNA damage responses and causes genotoxicity.

Single-stranded substrates of APOBEC3 deamination include single stranded intermediates at replication forks, DSBs, and those generated during break-induced replication. DNA mutations and breaks induced by APOBEC3 enzymes elicit DNA damage responses which may be specific to the template on which APOBEC3 acts. Replication fork collapse leading to DSBs, break-induced replication, and various patterns of mutations result from APOBEC3 activity on cellular DNA. DNA damage responses aid in recognition and repair of APOBEC3-induced lesions leading to cell cycle arrest, although APOBEC3 activity may overwhelm cellular responses leading to widespread mutations, replication fork collapse, DNA breaks, and cell death.

Figure 3.. APOBEC3 activity presents a therapeutic vulnerability in cancer cells.

APOBEC3 activity at replication structures recruits ATR and activates downstream signaling via phosphorylation of Chk1. When ATR signaling is intact (left panel), cell cycle arrest prior to mitosis enables repair of replication structures prior to cell division thus ensuring viable genome replication. If ATR signaling is inhibited (right panel), the DNA replication checkpoint is not activated and cells proceed to mitosis while accumulating mutations and breaks at replication forks. ATR inhibition in combination with APOBEC3 activity leads to mutations, collapse of replication forks, DNA breaks, and ultimately genotoxicity. Cellular dependence on ATR signaling when APOBEC3 enzymes are active exemplifies the potential for targeted therapeutics in tumors with high APOBEC3 activity.