Role of the single deaminase domain APOBEC3A in virus restriction, retrotransposition, DNA damage and cancer

Wang, Yaqiong; Schmitt, Kimberly; Guo, Kejun; Santiago, Mario L.; Stephens, Edward B.

doi:10.1099/jgv.0.000320

Cited by 19 publications

(14 citation statements)

References 157 publications

(185 reference statements)

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“…Furthermore, A3A itself can generate DNA breaks and activate the DNA Damage Response (DDR) (43,44) for which p53 is a major downstream regulator and effector (45). In our study, both WT and p53 mutant could upregulate A3A in response to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53

Menéndez

Nguyen

Snipe

et al. 2017

Molecular Cancer Research

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The APOBEC3 (A3) family of proteins are DNA cytidine deaminases that act as sentinels in the innate immune response against retroviral infections and are responsive to interferon. Recently, a few A3 genes were identified as potent enzymatic sources of mutations in several human cancers. Using human cancer cells and lymphocytes we show that under stress conditions and immune challenges all A3 genes are direct transcriptional targets of the tumor suppressor p53. While the expression of most A3 genes (including A3C and A3H) was stimulated by activation of p53, treatment with the DNA damaging agent doxorubicin or the p53 stabilizer Nutlin, led to repression of the A3B gene. Furthermore, p53 could enhance interferon type-I induction of A3 genes. Interestingly, overexpression of a group of tumor-associated p53 mutants in TP53-null cancer cells promoted A3B expression. These findings establish that the “guardian of the genome” role ascribed to p53 also extends to a unique component of the immune system–the A3 genes–thereby integrating human immune and chromosomal stress responses into an A3/p53 immune axis.

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Section: Discussionmentioning

confidence: 99%

The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53

Menéndez

Nguyen

Snipe

et al. 2017

Molecular Cancer Research

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“…The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15 ). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation

Westrich

Warren

Klausner

et al. 2018

J Virol

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APOBEC3 (A3) mutation signatures have been observed in a variety of human cancer genomes, including those of cervical and head and neck cancers caused by human papillomavirus (HPV) infection. However, the driving forces that promote off-target A3 activity remain mostly unclear. Here, we report a mechanism for the dramatic increase of A3A protein levels in HPV-positive keratinocytes. We show that expression of the viral protein E7 from high-risk HPVs, but not E7 from low-risk HPVs, significantly prolongs the cellular half-life of A3A protein in human keratinocytes and HPV-positive cancer cell lines. We have mapped several residues within the cullin 2 (CUL2) binding motif of HPV16 E7 as being important for mediating A3A protein stabilization. Furthermore, we provide direct evidence that both A3A and HPV16 E7 interact with CUL2, suggesting that the E7-CUL2 complex formed during HPV infection may regulate A3A protein levels in the cell. Using an in vitro cytidine deaminase assay, we show that E7-stabilized A3A remains catalytically active. Taken together, our findings suggest that the HPV oncoprotein E7 dysregulates endogenous A3A protein levels and thus provides novel mechanistic insight into cellular triggers of A3 mutations in HPV-positive cancers.IMPORTANCE Human papillomavirus (HPV) is causally associated with over 5% of all human malignancies. Several recent studies have shown that a subset of cancers, including HPV-positive head and neck and cervical cancers, have distinct mutational signatures potentially caused by members of the APOBEC3 cytidine deaminase family. However, the mechanism that induces APOBEC3 activity in cancer cells is poorly understood. Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner. Interestingly, the HPV E7-stabilized A3A protein maintains its deaminase activity. These findings provide a new insight into cancer mutagenesis enhanced by virus-induced A3A protein stabilization.

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“…The APOBEC3 protein family, comprising seven DNA cytidine deaminases (APOBEC3A, B, C, D, F, G, and H), plays an important role in the innate immune response to viral infections by editing viral genomes . A broad range of viruses has been reported to be restricted by APOBEC3A and APOBEC3B, including human immunodeficiency virus 1, parvovirus, herpesvirus, human papillomavirus, and HBV .…”

Section: Discussionmentioning

confidence: 99%

A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A

et al. 2019

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Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA(cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na + /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection. (Hepatology 2019;69:1885-1902). H epatitis B virus (HBV) infection is a worldwide health problem that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. (1,2) Recent studies estimated that the global prevalence of HBV surface antigen (HBsAg) in 2016 was 3.9%, with 291 million individuals with HBV infection. (3)

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Role of the single deaminase domain APOBEC3A in virus restriction, retrotransposition, DNA damage and cancer

Cited by 19 publications

References 157 publications

The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53

The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53

Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation

A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A

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