Alternative titles; symbols
HGNC Approved Gene Symbol: APOBEC3A
Cytogenetic location: 22q13.1 Genomic coordinates (GRCh38) : 22:38,957,609-38,963,184 (from NCBI)
Phorbolins-1 and -2 are highly expressed in psoriatic lesions. Treatment of normal keratinocytes with protein kinase C (PRKC; see 176960)-activating phorbol ester leads to the overexpression of both proteins. Using 2-dimensional gel electrophoresis, microsequence analysis, and screening of a psoriatic epidermis cDNA expression library with degenerate probes, Madsen et al. (1999) isolated a cDNA encoding phorbolin-1. The deduced 199-amino acid, 20-kD protein is 20% identical to APOBEC1 (600130) and has RNA-editing regions. However, phorbolin-1 neither complemented nor competed with APOBEC1 in RNA-editing assays. The protein also lacked cytidine deaminase (CDA; 123920) activity. Madsen et al. (1999) concluded that phorbolin-1 and phorbolin-1-related protein (607110) do not manifest any of the functional properties ascribed to APOBEC1.
Using RT-PCR, Bogerd et al. (2006) found that APOBEC3A was expressed only in peripheral blood leukocytes and spleen, whereas APOBEC3B (607110) was expressed at low levels in a wide range of somatic tissues and in undifferentiated human embryonic stem cell lines.
Bogerd et al. (2006) found that APOBEC3A and APOBEC3B inhibited LINE-1 retrotransposition in HeLa cells. APOBEC3A and APOBEC3B also inhibited Alu mobility, which is mediated by the LINE-1 ORF2 protein.
Three human APOBEC3 genes, APOBEC3A, APOBEC3B (607750), and APOBEC3H (610976), are expressed in keratinocytes and skin, leading Vartanian et al. (2008) to investigate whether genetic editing of human papillomavirus DNA occurred. In a study of HPV1a plantar warts and HPV16 precancerous cervical biopsies, hyperedited HPV1a and HPV16 genomes were found. Strictly analogous results were obtained from transfection experiments with HPV plasmid DNA and the 3 nuclear-localized enzymes APOBEC3A, APOBEC3B, and APOBEC3H. Thus, Vartanian et al. (2008) suggested that stochastic or transient overexpression of APOBEC3 genes may expose the genome to a broad spectrum of mutations that could influence the development of tumors.
Buisson et al. (2019) examined the mutation landscape in cancer genomes and found that many recurrent cancer mutations previously designated as drivers are likely passengers. The integrated bioinformatic and biochemical analyses revealed that these passenger hotspot mutations arise from the preference of APOBEC3A for DNA stem loops. Conversely, recurrent APOBEC-signature mutations not in stem loops were enriched in well-characterized driver genes and might predict new drivers. Buisson et al. (2019) argued that their results demonstrated that mesoscale genomic features need to be integrated into computational models aimed at identifying mutations linked to diseases.
By classifying diverse patterns of clustered mutagenesis in human tumor genomes, Mas-Ponte and Supek (2020) identified a novel APOBEC3 pattern of nonrecurrent, diffuse hypermutation that they called omikli, after the Greek word meaning 'fog.' This mechanism occurred independently of focal hypermutation, or kataegis (Greek for 'thunderstorm'), and was associated with activity of the DNA mismatch-repair (MMR) pathway. DNA MMR activity provided the single-stranded DNA substrates needed by APOBEC3 and contributed to a substantial proportion of APOBEC3 mutations genomewide. Because MMR was directed toward early-replicating, gene-rich chromosomal domains, APOBEC3 mutagenesis had a high propensity to generate impactful mutations, exceeding that of other common carcinogens, such as tobacco smoke and ultraviolet exposure. The authors concluded that cells direct their DNA repair capacity toward more important genomic regions, making carcinogens that subvert DNA repair highly potent.
Jarmuz et al. (2002) determined that the APOBEC3A gene contains 5 exons.
Using FISH and cosmid analyses, Madsen et al. (1999) mapped the phorbolin-1 gene to chromosome 22q13, close to the phorbolin-1-related gene and centromeric to the PDGFB gene (190040).
By FISH and genomic sequence analysis, Jarmuz et al. (2002) mapped the APOBEC3A gene within a tandem array of 7 APOBEC genes or pseudogenes on chromosome 22q12-q13.2. All are oriented with a centromeric 5-prime end. The authors noted that a similar expansion of the APOBEC family is not present in rodents.
Bogerd, H. P., Wiegand, H. L., Hulme, A. E., Garcia-Perez, J. L., O'Shea, K. S., Moran, J. V., Cullen, B. R. Cellular inhibitors of long interspersed element 1 and Alu retrotransposition. Proc. Nat. Acad. Sci. 103: 8780-8785, 2006. [PubMed: 16728505] [Full Text: https://doi.org/10.1073/pnas.0603313103]
Buisson, R., Langenbucher, A., Bowen, D., Kwan, E. E., Benes, C. H., Zou, L., Lawrence, M. S. Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features. Science 364: eaaw2872, 2019. Note: Electronic Article. [PubMed: 31249028] [Full Text: https://doi.org/10.1126/science.aaw2872]
Jarmuz, A., Chester, A., Bayliss, J., Gisbourne, J., Dunham, I., Scott, J., Navaratnam, N. An anthropoid-specific locus of orphan C to U RNA-editing enzymes on chromosome 22. Genomics 79: 285-296, 2002. [PubMed: 11863358] [Full Text: https://doi.org/10.1006/geno.2002.6718]
Madsen, P., Anant, S., Rasmussen, H. H., Gromov, P., Vorum, H., Dumanski, J. P., Tommerup, N., Collins, J. E., Wright, C. L., Dunham, I., MacGinnitie, A. J., Davidson, N. O., Celis, J. E. Psoriasis upregulated phorbolin-1 shares structural but not functional similarity to the mRNA-editing protein apobec-1. J. Invest. Derm. 113: 162-169, 1999. [PubMed: 10469298] [Full Text: https://doi.org/10.1046/j.1523-1747.1999.00682.x]
Mas-Ponte, D., Supek, F. DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers. Nature Genet. 52: 958-968, 2020. [PubMed: 32747826] [Full Text: https://doi.org/10.1038/s41588-020-0674-6]
Vartanian, J.-P., Guetard, D., Henry, M., Wain-Hobson, S. Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science 320: 230-233, 2008. [PubMed: 18403710] [Full Text: https://doi.org/10.1126/science.1153201]