APOBEC3A (Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 3A)

A panel of herpesviral ribonucleotide reductase constructs was used to show that direct inhibition of APOBEC3A results in a dose-responsive recovery of firefly luciferase expression. HAMMER is therefore a scalable and easy-to-use method for quantifying cellular APOBEC3A RNA editing activity and characterizing inhibitors.

These associations were independently validated in additional cohorts using routine complete blood count testing and multiplex immunofluorescence analysis of native tumor tissues. Our findings reveal monocyte-related parameters as clinically accessible indicators that link systemic immunity with the tumor microenvironment and hold promise for predicting IC responsiveness in patients with LUSC.

The APOBEC3A-like editing motif also prevailed in the RNA genomes of SARS-CoV-2 pandemic isolates, as well as in infectious persistent rubella viruses, and in polioviruses emerging from live-attenuated vaccine strains. Together, our results indicate that APOBEC3A is the predominant global APOBEC RNA editor with a potential to impact cell physiology and viral evolution.

APOBEC exhibits distinct driving mechanisms in HNSCC depending on HPV status. Its activity is closely related to cGAS-STING pathway activation, enhanced immune infiltration, and improved immunotherapy efficacy, suggesting potential predictive and therapeutic value.

Finally, we found that a germline APOBEC3A/B copy-number deletion was more prevalent in H/L than in NHW and was associated with the COSMIC APOBEC mutational signatures and with CE10 ecotype. Overall, these results suggest that ancestry differences may provide insights into specific mutation and immune profiles.

Non-cancerous diseased samples showed significantly higher, age-independent accumulation of aTn and nCg motifs compared to healthy tissues. Together, our analyses elucidated several ongoing mutagenic processes in normal human tissues and provided a robust analytical framework for identifying mutagenic sources from somatic mutation catalogues.

APOBEC3-mediated mutagenesis is discussed as a mechanistic link between genomic instability and tumor-immune crosstalk in solid tumors, with emphasis on its relationships to immunoediting, immune checkpoint pathways, and therapeutic responses. Context-dependent associations of APOBEC3 activity with immune activation or immune evasion are also considered, together with their implications for strategies that modulate this pathway.

All together, our findings reveal a novel interferon-independent signalling route through which hypoxia-induced mitochondrial stress activates A3A, directly linking metabolic dysfunction to genome instability. This mechanism involves mitochondrial perturbation as a key driver of APOBEC3-mediated mutagenesis in hypoxic tumours and other diseases associated with mitochondrial stress.

A panel of herpesviral ribonucleotide reductase constructs was used to show that direct inhibition of APOBEC3A results in a dose-responsive recovery of firefly luciferase expression. HAMMER is therefore a scalable and easy-to-use method for quantifying cellular APOBEC3A RNA editing activity and characterizing inhibitors.

The APOBEC3A-like editing motif also prevailed in the RNA genomes of SARS-CoV-2 pandemic isolates, as well as in infectious persistent rubella viruses, and in polioviruses emerging from live-attenuated vaccine strains. Together, our results indicate that APOBEC3A is the predominant global APOBEC RNA editor with a potential to impact cell physiology and viral evolution.

Consistent with tumor data, RNA-seq showed upregulation of tumor enhancing pathways only in cells that enhanced tumor progression. The results indicate that in a breast cancer xenograft model, APOBEC3A and APOBEC3H Haplotype I are more likely to contribute to enhanced tumor progression than APOBEC3B.

Multi-cohort replication showed robust findings in European ancestry populations, while transferability to other populations was more limited. This work demonstrates the value of a gene-centric, integrative framework for prioritizing high-confidence BC predisposition genes, highlighting associated cellular pathways, and uncovering new candidates for further functional study, providing a reliable foundation for future research.