APOBEC3s: DNA‐editing human cytidine deaminases

Silvas, Tania V.; Schiffer, Celia A.

doi:10.1002/pro.3670

Cited by 54 publications

(57 citation statements)

References 93 publications

(197 reference statements)

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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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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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“…The A3 locus of human, other hominoids, and Old World monkeys comprises seven clustered genes, A3A-A3H (Jarmuz et al, 2002;OhAinle et al, 2006;Silvas and Schiffer, 2019) ( Figure 1A). We undertook an analysis to search for any variation in this gene structure in other primate genomes.…”

Section: A3i: An Ancient A3 Retrocopy In Simian Primatesmentioning

confidence: 99%

Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates

Yang

Emerman

Malik

et al. 2020

Preprint

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Infectious viruses and selfish genetic elements impose fitness costs on host genomes. To counteract the deleterious effects of such pathogens, host genomes deploy restriction factors such as APOBEC3 (A3) cytidine deaminases. Host genomes must also continually adapt their restriction factors to keep pace with the dynamic evolution of pathogens. For example, the mammalian A3 gene family has undergone positive selection and expansion via segmental gene duplication and recombination. Here, we show that the A3 gene family has further diversified in primates via retrocopying. First, we discovered that all simian primate genomes retain the remnants of an ancient A3 retrocopy: A3I. Furthermore, we found that some New World monkeys encode up to ten additional APOBEC3G (A3G) retrocopies. Some of these A3G retrocopies are transcribed in a variety of tissues and able to restrict retroviruses.Our findings suggest that retrocopying enables host genomes to co-opt retroelement activity in the germline to create new host restriction factors that may block the deleterious effects of viruses. (162)

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“…The type of transition and the relative abundance of the C36U and C241U variations suggest they might be hot spots for viral genome editing by host defense enzymes. The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) enzymes are host encoded cytidine deaminases that edit cytidine to uridine in host nucleic acids (Lerner et al 2018;Silvas and Schiffer 2019). They also target single stranded RNA and DNA virus genomes to affect an antiviral response.…”

Section: Variations In the 5´utr That Could Have Arisen Through Rna Ementioning

confidence: 99%

Analysis of Rapidly Emerging Variants in Structured Regions of the SARS-CoV-2 Genome

Ryder¹

2020

Preprint

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AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has motivated a widespread effort to understand its epidemiology and pathogenic mechanisms. Modern high-throughput sequencing technology has led to the deposition of vast numbers of SARS-CoV-2 genome sequences in curated repositories, which have been useful in mapping the spread of the virus around the globe. They also provide a unique opportunity to observe virus evolution in real time. Here, we evaluate two cohorts of SARS-CoV-2 genomic sequences to identify rapidly emerging variants within structured cis-regulatory elements of the SARS-CoV-2 genome. Overall, twenty variants are present at a minor allele frequency of at least 0.5%. Several enhance the stability of Stem Loop 1 in the 5’UTR, including a set of co-occurring variants that extend its length. One appears to modulate the stability of the frameshifting pseudoknot between ORF1a and ORF1b, and another perturbs a bi-stable molecular switch in the 3’UTR. Finally, five variants destabilize structured elements within the 3’UTR hypervariable region, including the S2M stem loop, raising questions as to the functional relevance of these structures in viral replication. Two of the most abundant variants appear to be caused by RNA editing, suggesting host-viral defense contributes to SARS-CoV-2 genome heterogeneity. This analysis has implications for the development of therapeutics that target viral cis-regulatory RNA structures or sequences, as rapidly emerging variations in these regions could lead to drug resistance.

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APOBEC3s: DNA‐editing human cytidine deaminases

Cited by 54 publications

References 93 publications

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

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

Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates

Analysis of Rapidly Emerging Variants in Structured Regions of the SARS-CoV-2 Genome

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