Alternative titles; symbols
HGNC Approved Gene Symbol: APOBEC3B
Cytogenetic location: 22q13.1 Genomic coordinates (GRCh38) : 22:38,982,347-38,992,779 (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. By comparing the sequence of phorbolin-1 (APOBEC3A; 607109) with other cDNAs isolated from a psoriatic epidermis cDNA expression library, Madsen et al. (1999) obtained a cDNA encoding phorbolin-1-related protein and at least 1 variant that uses an alternative AUG. The deduced 235-amino acid, 28-kD protein is 89% identical to phorbolin-1, with most differences at the N terminus. Like phorbolin-1, phorbolin-1-related protein contains an RNA-editing region but fails to bind apolipoprotein B (APOB; 107730) mRNA. Madsen et al. (1999) concluded that the phorbolin proteins do not manifest any of the functional properties ascribed to APOBEC1 (600130).
By Northern blot analysis, Jarmuz et al. (2002) determined that APOBEC3B is expressed primarily in peripheral blood leukocytes, and it was detected in most tumor cell lines examined.
Using RT-PCR, Bogerd et al. (2006) found that APOBEC3A was expressed only in peripheral blood leukocytes and spleen, whereas APOBEC3B was expressed at low levels in a wide range of somatic tissues and in undifferentiated human embryonic stem cell lines.
Jarmuz et al. (2002) determined that recombinant APOBEC3B expressed in insect cells bound zinc and dimerized with APOBEC3G (607113), but not with APOBEC1. APOBEC3B did not edit APOB, NF1 (613113), or NAT1 (108345) mRNAs.
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.
Burns et al. (2013) showed that the DNA cytosine deaminase APOBEC3B is a probable source of somatic C-to-T mutations in breast cancer (114480). APOBEC3B mRNA is upregulated in most primary breast tumors and breast cancer cell lines. Tumors that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53 (191170). Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Knockdown experiments showed that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression caused cell cycle deviations, cell death, DNA fragmentation, gamma-H2AX (601772) accumulation, and C-to-T mutations. Burns et al. (2013) concluded that their data suggested a model in which APOBEC3B-catalyzed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explained how some tumors evolve rapidly and manifest heterogeneity.
Following up on the report of Burns et al. (2013), which found that APOBEC3B accounts for up to half of the mutational load in breast carcinomas expressing this enzyme, Burns et al. (2013) addressed whether APOBEC3B is broadly responsible for mutagenesis in multiple tumor types. They analyzed gene expression data and mutation patterns, distributions, and loads for 19 different cancer types, with over 4,800 exomes and 1,000,000 somatic mutations. In at least 6 distinct cancers (bladder, cervix, lung adenocarcinoma, lung squamous cell carcinoma, head and neck, and breast), APOBEC3B is upregulated, its preferred target sequence is frequently mutated, and these mutations are clustered (kataegis). Interpreting these findings in the light of previous genetic, cellular, and biochemical studies, Burns et al. (2013) suggested that the most parsimonious conclusion from these global analyses is that APOBEC3B-catalyzed genomic uracil lesions are responsible for a large proportion of both dispersed and clustered mutations in multiple distinct cancers.
Maciejowski et al. (2020) examined the mechanism underlying chromothripsis and kataegis using an in vitro telomere crisis model in human cells and showed that the cytoplasmic exonuclease TREX1 (606609), which promotes resolution of dicentric chromosomes, played a prominent role in chromothriptic fragmentation. In the absence of TREX1, genome alterations induced by telomere crisis primarily involved breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Kataegis observed at chromothriptic breakpoints was due to cytosine deamination by APOBEC3B. Maciejowski et al. (2020) concluded that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.
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 APOBEC3B gene contains 8 exons. The 5-prime untranslated region and the 5-prime flanking region contain repeated sequences. No TATA or CATT box was identified.
Using FISH and cosmid analyses, Madsen et al. (1999) mapped the phorbolin-1-related gene to chromosome 22q13, close to the phorbolin-1 gene and centromeric to the PDGFB gene (190040).
By FISH and genomic sequence analysis, Jarmuz et al. (2002) mapped the APOBEC3B 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.
Marchetto et al. (2013) described the generation and initial characterization of induced pluripotent stem (iPS) cells from chimpanzees and bonobos as tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and nonhuman primate iPS cells revealed differences in the regulation of long interspersed element-1 (L1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B and PIWIL2 (610312) in nonhuman primate iPS cells correlated with increased L1 mobility and endogenous L1 mRNA levels. Moreover, results from the manipulation of APOBEC3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, Marchetto et al. (2013) found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in nonhuman primates is not limited to iPS cells in culture and may have also occurred in the germline or embryonic cells developmentally upstream to germline specification during primate evolution. Marchetto et al. (2013) proposed that differences in L1 mobility may have differentially shaped the genomes of humans and nonhuman primates and could have continuing adaptive significance.
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]
Burns, M. B., Lackey, L., Carpenter, M. A., Rathore, A., Land, A. M., Leonard, B., Refsland, E. W., Kotandeniya, D., Tretyakova, N., Nikas, J. B., Yee, D., Temiz, N. A., Donohue, D. E., McDougle, R. M., Brown, W. L., Law, E. K., Harris, R. S. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494: 366-370, 2013. Note: Erratum: Nature 502: 580 only, 2013. [PubMed: 23389445] [Full Text: https://doi.org/10.1038/nature11881]
Burns, M. B., Temiz, N. A., Harris, R. S. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genet. 45: 977-983, 2013. [PubMed: 23852168] [Full Text: https://doi.org/10.1038/ng.2701]
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]
Maciejowski, J., Chatzipli, A., Dananberg, A., Chu, K., Toufektchan, E., Klimczak, L. J., Gordenin, D. A., Campbell, P. J., de Lange, T. APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis. Nature Genet. 52: 884-890, 2020. [PubMed: 32719516] [Full Text: https://doi.org/10.1038/s41588-020-0667-5]
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]
Marchetto, M. C. N., Narvaiza, I., Denli, A. M., Benner, C., Lazzarini, T. A., Nathanson, J. L., Paquola, A. C. M., Desai, K. N., Herai, R. H., Weitzman, M. D., Yeo, G. W., Muotri, A. R., Gage, F. H. Differential L1 regulation in pluripotent stem cells of humans and apes. Nature 503: 525-529, 2013. [PubMed: 24153179] [Full Text: https://doi.org/10.1038/nature12686]
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]