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

Green, Abby M.; Weitzman, Matthew D.

doi:10.1016/j.dnarep.2019.102700

Cited by 74 publications

(71 citation statements)

References 115 publications

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“…There are 11 APOBEC/AID ORFs encoded in human genome. Seven proteins encoded by APOBEC3 gene cluster and the APOBEC1 encoded by a gene located on a different chromosome have demonstrated ssDNA-specific cytidine deaminase activity [71,72]. In agreement with various model system studies on mutagenesis induced by the APOBEC enzymes, in cancers with a high enrichment of the APOBEC-specific tCw→T or tCw→G changes, C-or G-coordinated clustered mutations were also found to carry tCw→T or tCw→G changes (w = A or T, mutated base capitalized).…”

Section: Hypermutation In Cancers By the Apobec Cytidine Deaminasessupporting

confidence: 75%

Hypermutation in single-stranded DNA

Saini

Gordenin

2020

DNA Repair

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Regions of genomic DNA can become single-stranded in the course of normal replication and transcription as well as during DNA repair. Abnormal repair and replication intermediates can contain large stretches of persistent single-stranded DNA, which is extremely vulnerable to DNA damaging agents and hypermutation. Since such single-stranded DNA spans only a fraction of the genome at a given instance, hypermutation in these regions leads to tightly-spaced mutation clusters. This phenomenon of hypermutation in single-stranded DNA has been documented in several experimental models as well as in cancer genomes. Recently, hypermutated single-stranded RNA viral genomes also have been documented. Moreover, indications of hypermutation in single-stranded DNA may also be found in the human germline. This review will summarize key current knowledge and the recent developments in understanding the diverse mechanisms and sources of ssDNA hypermutation.

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Section: Hypermutation In Cancers By the Apobec Cytidine Deaminasessupporting

confidence: 75%

Hypermutation in single-stranded DNA

Saini

Gordenin

2020

DNA Repair

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“…Interestingly, linkage and association studies have linked the CDKN2A locus (9p21.3) to late-onset AD families [ 30 ]. Human APOBEC3 plays important roles in intracellular defense against viral infection and cancer development by generating DNA mutations [ 31 ]. However, no previous studies have found associations between APOBEC3 and AD.…”

Section: Discussionmentioning

confidence: 99%

Identifying Blood Transcriptome Biomarkers of Alzheimer’s Disease Using Transgenic Mice

et al. 2020

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The testing of pathological biomarkers of Alzheimer’s disease (AD), such as amyloid beta and tau, is time-consuming, expensive, and invasive. Here, we used 3xTg-AD mice to identify and validate putative novel blood transcriptome biomarkers of AD that can potentially be identified in the blood of patients. mRNA was extracted from the blood and hippocampus of 3xTg-AD and control mice at different ages and used for microarray analysis. Network and functional analyses revealed that the differentially expressed genes between AD and control mice modulated the immune and neuroinflammation systems. Five novel gene transcripts (Cdkn2a, Apobec3, Magi2, Parp3, and Cass4) showed significant increases with age, and their expression in the blood was collated with that in the hippocampus only in AD mice. We further assessed previously identified candidate biomarker genes. The expression of Trem1 and Trem2 in both the blood and brain was significantly increased with age. Decreased Tomm40 and increased Pink1 mRNA levels were observed in the mouse blood. The changes in the expression of Snca and Apoe mRNA in the mouse blood and brain were similar to those found in human AD blood. Our results demonstrated that the immune and neuroinflammatory system is involved in the pathophysiologies of aging and AD and that the blood transcriptome might be useful as a biomarker of AD.

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“…The human APOBEC family has nine active family members: APOBEC1, AID, and APOBEC3A/B/C/D/F/G/H [reviewed by (Green & Weitzman, 2019;Harris & Dudley, 2015;Ito, Gifford, & Sato, 2020;Olson, Harris, & Harki, 2018;Silvas & Schiffer, 2019;Simon, Bloch, & Landau, 2015;Siriwardena, Chen, & Bhagwat, 2016)]. Although several APOBEC3s have been implicated in cancer mutagenesis including APOBEC3A (A3A) and APOBEC3H (A3H) (Chan et al, 2015;Nik-Zainal et al, 2014;Starrett et al, 2016;Taylor et al, 2013), a particularly strong case can be made for APOBEC3B (A3B).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B

Roelofs

Goh

Chua

et al. 2020

eLife

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APOBEC3B (A3B)-catalyzed DNA cytosine deamination contributes to the overall mutational landscape in breast cancer. Molecular mechanisms responsible for A3B upregulation in cancer are poorly understood. Here, we show that a single E2F cis-element mediates repression in normal cells and that expression is activated by its mutational disruption in a reporter construct or the endogenous A3B gene. The same E2F site is required for A3B induction by polyomavirus T antigen indicating a shared molecular mechanism. Proteomic and biochemical experiments demonstrate binding of wildtype but not mutant E2F promoters by repressive PRC1.6/E2F6 and DREAM/E2F4 complexes. Knockdown and overexpression studies confirm involvement of these repressive complexes in regulating A3B expression. Altogether, these studies demonstrate that A3B expression is suppressed in normal cells by repressive E2F complexes and that viral or mutational disruption of this regulatory network triggers overexpression in breast cancer and provides fuel for tumor evolution.

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

Cited by 74 publications

References 115 publications

Hypermutation in single-stranded DNA

Hypermutation in single-stranded DNA

Identifying Blood Transcriptome Biomarkers of Alzheimer’s Disease Using Transgenic Mice

Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B

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