APOBEC3A can activate the DNA damage response and cause cell‐cycle arrest

Abstract

Human apolipoprotein-B mRNA-editing catalytic polypeptidelike 3 (APOBEC3) proteins constitute a family of cytidine deaminases that mediate restriction of retroviruses, endogenous retro-elements and DNA viruses. It is well established that these enzymes are potent mutators of viral DNA, but it is unclear whether their editing activity is a threat to the integrity of the cellular genome. We show that expression of APOBEC3A can lead to induction of DNA breaks and activation of damage responses in a deaminase-dependent manner. Consistent with these observations, APOBEC3A expression induces cell-cycle arrest. These results indicate that cellular DNA is vulnerable to APOBEC3 activity and deregulated expression of APOBEC3A could threaten genomic integrity.

Endogenous APOBEC3A DNA Cytosine Deaminase Is Cytoplasmic and Nongenotoxic

“…Overexpressed Heterologous A3A Is Genotoxic, whereas Upregulated Physiologic A3A Is Safely Expressed-A3A overexpression has been reported to be genotoxic (22,23,26). To characterize the extent of A3A toxicity, we employed a doxycycline-inducible system to regulate A3A expression levels.…”

“…However, A3A has also been shown to be genotoxic under conditions of overexpression (22,23,26) and to mutate genomic DNA (24,25). CD14 ϩ cells are known to express high levels of A3A upon type I IFN induction (4,6,7), suggesting that these cells must either have a mechanism for regulating A3A activity or be subject to its genotoxic effects.…”

“…Beyond these restriction activities, A3A has been suggested to have a role in cancer, due to its genotoxic capacity (22,23). Overexpressed A3A has been shown to cause chromosomal DNA damage and mutation (22)(23)(24)(25)(26) as well as disruption of the cell cycle (22,26).…”

“…Overexpressed A3A has been shown to cause chromosomal DNA damage and mutation (22)(23)(24)(25)(26) as well as disruption of the cell cycle (22,26). Expression of A3A in a cell threatens genomic integrity, suggesting that uncontrolled activation of this immune defense molecule would have undesirable consequences.…”

APOBEC3 proteins and genomic stability

“…In a recent study, we reported that A3A expression can induce DNA breaks and activate the cellular DNA damage response (DDR) in a deaminasedependent fashion. 31 The DDR induced by A3A was revealed using antibodies generated to specific phosphorylation marks on DNA damage/repair proteins (such as the histone variant H2AX), 32 and DNA breaks were detected using the terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay. In addition, using a UNG inhibitor (UGI), we demonstrated that UNG activity is required for both A3A-induced DNA breaks and activation of the DDR, suggesting that DNA damage signaling occurs as a consequence of cellular processing of A3A-induced uracil lesions.…”