RNA editing enzyme APOBEC3A promotes pro-inflammatory M1 macrophage polarization

Alqassim, Emad; Sharma, Shraddha; Khan, Aalia; Emmons, Tiffany R.; Gomez, Eduardo Cortes; Alahmari, Abdulrahman A.; Singel, Kelly L.; Mark, Jaron; Davidson, Bruce A.; McGray, AJ Robert; Liu, Qian; Lichty, Brian D.; Moysich, Kirsten B.; Wang, Jianmin; Odunsi, Kunle; Segal, Brahm H.; Baysal, Bora E.

doi:10.1038/s42003-020-01620-x

Cited by 38 publications

(39 citation statements)

References 55 publications

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“…The A3 family of enzymes are all cytosine deaminases on ssDNA, although some can also deaminate RNA [31,35]. In primates, there are at least seven members in the A3 family [36].…”

Section: Overview Of Apobec3smentioning

confidence: 99%

Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses

Gaba

Flath

Chelico

2021

Viruses

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The transmission of viruses from animal hosts into humans have led to the emergence of several diseases. Usually these cross-species transmissions are blocked by host restriction factors, which are proteins that can block virus replication at a specific step. In the natural virus host, the restriction factor activity is usually suppressed by a viral antagonist protein, but this is not the case for restriction factors from an unnatural host. However, due to ongoing viral evolution, sometimes the viral antagonist can evolve to suppress restriction factors in a new host, enabling cross-species transmission. Here we examine the classical case of this paradigm by reviewing research on APOBEC3 restriction factors and how they can suppress human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). APOBEC3 enzymes are single-stranded DNA cytidine deaminases that can induce mutagenesis of proviral DNA by catalyzing the conversion of cytidine to promutagenic uridine on single-stranded viral (−)DNA if they escape the HIV/SIV antagonist protein, Vif. APOBEC3 degradation is induced by Vif through the proteasome pathway. SIV has been transmitted between Old World Monkeys and to hominids. Here we examine the adaptations that enabled such events and the ongoing impact of the APOBEC3-Vif interface on HIV in humans.

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“…The A3 family of enzymes are all cytosine deaminases on ssDNA, although some can also deaminate RNA [31,35]. In primates, there are at least seven members in the A3 family [36].…”

Section: Overview Of Apobec3smentioning

confidence: 99%

Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses

Gaba

Flath

Chelico

2021

Viruses

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“…Previous studies have shed some light into the potential mechanisms governing A3A's substrate specificity. While there is speculation that RNA deamination may be a physiological role for A3A, 16 the only APOBEC family member for which RNA activity is definitively established is APOBEC1. 17 Nonetheless, most family members have been shown to bind RNA even tighter than DNA, 18 adding to the enigma of nucleic acid selectivity.…”

Section: Introductionmentioning

confidence: 99%

The base-editing enzyme APOBEC3A catalyzes cytosine deamination in RNA with low proficiency and high selectivity

Barka

Berríos

Bailer

et al. 2021

Preprint

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Human APOBEC3A (A3A) is a nucleic acid-modifying enzyme that belongs to the cytidine deaminase family. Canonically, A3A catalyzes the deamination of cytosine into uracil in single-stranded DNA, an activity that makes A3A both a critical antiviral defense factor and a useful tool for targeted genome editing. However, off-target mutagenesis by A3A has been readily detected in both cellular DNA and RNA, which has been shown to promote oncogenesis. Given the importance of substrate discrimination for the physiological, pathological, and biotechnological activities of A3A, here we explore the mechanistic basis for its preferential targeting of DNA over RNA. Using a chimeric substrate containing a target ribocytidine within an otherwise DNA backbone, we demonstrate that a single hydroxyl at the sugar of the target base acts as a major selectivity determinant for deamination. To assess the contribution of bases neighboring the target cytosine, we show that overall RNA deamination is greatly reduced relative to that of DNA, but can be observed when ideal features are present, such as preferred sequence context and secondary structure. A strong dependence on idealized substrate features can also be observed with a mutant of A3A (eA3A, N57G) which has been employed for genome editing due to altered selectivity for DNA over RNA. Altogether, our work reveals a relationship between the overall decreased reactivity of A3A and increased substrate selectivity, and our results hold implications both for characterizing off-target mutagenesis and for engineering optimized DNA deaminases for base-editing technologies.

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“…Notably, APOBEC activity has also been linked to antibody diversification and one may thus speculate that a slight increase in APOBEC activity may lead to a more diversified and/or adaptable immune system providing better tumour suppression 38 – 40 . More recently, it has been found that APOBEC3A is able to induce RNA editing in monocytes and macrophages 41 , and it has been reported that APOBEC3A promotes M1 macrophage polarization 42 , further indicating roles for APOBEC activity in relation to immune response activity.…”

Section: Discussionmentioning

confidence: 99%

Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer

Gansmo

Sofiyeva

Bjørnslett

et al. 2021

Sci Rep

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A germline 29.5-kb deletion variant removes the 3’ end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in hospital-based samples of 1398 Norwegian epithelial ovarian cancer patients without detected BRCA1/2 germline mutations and compared to 1,918 healthy female controls, to assess the potential cancer risk associated with the deletion. We observed an association between APOBEC3A/B status and reduced risk for ovarian cancer (OR = 0.75; CI = 0.61–0.91; p = 0.003) applying the dominant model. Similar results were found in other models. The association was observed both in non-serous and serous cases (dominant model: OR = 0.69; CI = 0.50–0.95; p = 0.018 and OR = 0.77; CI = 0.62–0.96; p = 0.019, respectively) as well as within high-grade serous cases (dominant model: OR = 0.79; CI = 0.59–1.05). For validation purposes, we mined an available large multinational GWAS-based data set of > 18,000 cases and > 26,000 controls for SNP rs12628403, known to be in linkage disequilibrium with the APOBEC3A/B deletion. We found a non-significant trend for SNP rs12628403 being linked to reduced risk of ovarian cancer in general and similar trends for all subtypes. For clear cell cancers, the risk reduction reached significance (OR = 0.85; CI = 0.69–1.00).

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RNA editing enzyme APOBEC3A promotes pro-inflammatory M1 macrophage polarization

Cited by 38 publications

References 55 publications

Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses

Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses

The base-editing enzyme APOBEC3A catalyzes cytosine deamination in RNA with low proficiency and high selectivity

Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer

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