Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage

Suspène, Rodolphe; Mußil, Bianka; Laude, Hélène; Caval, Vincent; Berry, Noémie; Bouzidi, Mohamed S.; Thiers, Valérie; Wain‐Hobson, Simon; Vartanian, Jean‐Pierre

doi:10.1093/nar/gkx001

Cited by 27 publications

(67 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Upregulation of APOBEC3 protein expression was previously shown to be dependent on interferon alpha, and it is associated with non-cytolytic clearance of human hepatitis B virus in primary hepatocytes 32 . Cytoplasmic DNA triggers production of type I interferon, leading to massive upregulation of APOBEC3A 33,34 . Here, we investigated the effects of different APOBEC3 proteins, and found that expression of A3C, A3F or A3H limits coronavirus infection.…”

Section: Discussionmentioning

confidence: 99%

APOBEC3-mediated restriction of RNA virus replication

Milewska

Kindler

V’kovski

et al. 2018

Sci Rep

113

106

View full text Add to dashboard Cite

APOBEC3 family members are cytidine deaminases with roles in intrinsic responses to infection by retroviruses and retrotransposons, and in the control of other DNA viruses, such as herpesviruses, parvoviruses and hepatitis B virus. Although effects of APOBEC3 members on viral DNA have been demonstrated, it is not known whether they edit RNA genomes through cytidine deamination. Here, we investigated APOBEC3-mediated restriction of Coronaviridae. In experiments in vitro, three human APOBEC3 proteins (A3C, A3F and A3H) inhibited HCoV-NL63 infection and limited production of progeny virus, but did not cause hypermutation of the coronaviral genome. APOBEC3-mediated restriction was partially dependent on enzyme activity, and was reduced by the use of enzymatically inactive APOBEC3. Moreover, APOBEC3 proteins bound to the coronaviral nucleoprotein, and this interaction also affected viral replication. Although the precise molecular mechanism of deaminase-dependent inhibition of coronavirus replication remains elusive, our results further our understanding of APOBEC-mediated restriction of RNA virus infections.

show abstract

Section: Discussionmentioning

confidence: 99%

APOBEC3-mediated restriction of RNA virus replication

Milewska

Kindler

V’kovski

et al. 2018

Sci Rep

113

106

View full text Add to dashboard Cite

show abstract

“…). In the APOBEC3 family, A3B and A3H localize to the nucleus, while A3A and A3G are transiently recruited to the nucleus . When overexpressed, A3B and A3H have been described as a major endogenous source for mutations in various types of human cancer, such as breast, bladder, head and neck, cervical, and lung cancer .…”

Section: Introductionmentioning

confidence: 99%

APOBEC3s: DNA‐editing human cytidine deaminases

Silvas

Schiffer

2019

Protein Science

View full text Add to dashboard Cite

Nucleic acid editing enzymes are essential components of the human immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins. Among these enzymes are cytidine deaminases of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) super family, each with unique target sequence specificity and subcellular localization. We focus on the DNA‐editing APOBEC3 enzymes that have recently attracted attention because of their involvement in cancer and potential in gene‐editing applications. We review and compare the crystal structures of APOBEC3 (A3) domains, binding interactions with DNA, substrate specificity, and activity. Recent crystal structures of A3A and A3G bound to ssDNA have provided insights into substrate binding and specificity determinants of these enzymes. Still many unknowns remain regarding potential cooperativity, nucleic acid interactions, and systematic quantification of substrate preference of many APOBEC3s, which are needed to better characterize the biological functions and consequences of misregulation of these gene editors.

show abstract

“…In RNA, where uracil has a coding function, deamination is an RNA editing tool. In DNA, the formation of uracil by APOBEC/AID is a promutagenic lesion which in some cases can be detrimental and cause cancer, but in other cases enables evolution of antibody genes and inactivation of viruses, retroelement, or other cytoplasmic inflammation-inducing DNA [5,11,12].…”

Section: Apobec Family Of Enzymesmentioning

confidence: 99%

“…can deaminate incoming foreign DNA or stress associated cytoplasmic dsDNA released from mitochondria [12,195,196], and this may play a role in modulating dsDNA induced inflammation. Cytoplasmic dsDNA can activate RIG-I inflammatory pathways if it is transcribed into dsRNA by RNA polymerase III [12].…”

Section: Role Of Apobec In Somatic Mutagenesismentioning

confidence: 99%

“…Cytoplasmic dsDNA can activate RIG-I inflammatory pathways if it is transcribed into dsRNA by RNA polymerase III [12]. A3 enzymes presumably inhibits this proinflammatory process by deaminating the ssDNA generated during transcription, which leads to DNA degradation by UNG, or prevents reannealing of the DNA strands [12].…”

Section: Role Of Apobec In Somatic Mutagenesismentioning

confidence: 99%

See 1 more Smart Citation

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

2018

View full text Add to dashboard Cite

Apolipoprotein B mRNA-editing enzyme-catalytic, polypeptide-like 3 (APOBEC3) enzymes are a family of single-stranded (ss)DNA cytosine deaminases that serve as a host restriction factors for retrotransposons and viruses that contain a ssDNA intermediate. While the APOBEC3 family was originally expanded to restrict endogenous retroelements, the majority of these targets are now inactivated and the family has been found to act on different targets, such as viral ssDNA as a mechanism of viral defense. Some of the family members also catalyze "offtarget" deaminations in human ssDNA and have been implicated in somatic mutagenesis that can lead to cancer.My PhD thesis research investigated the biochemical mechanisms underlying both the benefits and the risks of the A3 family of enzymes. The central hypothesis of this work is that A3 enzymes have evolved distinct biochemical mechanisms to deaminate ssDNA that differentiate A3 restriction of retroelements and retroviruses from A3-induced somatic mutagenesis.Therefore, we investigated the biochemical mechanisms the A3 enzymes utilize during restriction of Human Immunodeficiency Virus (HIV) in both deamination-dependent and deaminationindependent modes, as well as the unique mechanisms employed during mutation of genomic DNA. There are seven APOBEC3 members (A-H, excluding E) and of these, four members (A3D, A3F, A3G, A3H) have been identified to restrict HIV replication in CD4 T+ cells, and currently three members (A3A, A3B and A3H haplotype I) have been implicated in somatic mutagenesis.The APOBEC3 enzymes that restrict HIV replication function optimally in the absence of the HIV viral infectivity factor (Vif). Vif targets APOBEC3 for degradation via the proteasome in HIV infected cells. For APOBEC3s that are able to fortuitously escape Vif mediated degradation and become encapsidated, the enzymes can deaminate cytosines to form uracils in viral (-)DNA. Replication of (-)DNA to (+)DNA causes HIV-1 reverse transcriptase to incorporate adenines opposite uracils which creates C/G→T/A transition mutations. While restriction of HIV most commonly occurs through this deamination-dependent mechanism, APOBEC3s have also been identified to interfere with HIV reverse transcriptase processes in a deamination-independent manner, although this mechanism is secondary to the deaminationdependent mode. In order to restrict retroelements and viruses such as HIV, the A3 enzymes iii require an efficient processive ssDNA scanning mechanism that allows them to search for, and locate cytosines on ssDNA in the finite amount of time the substrate is available during formation of the double-stranded DNA provirus. To understand if this requirement was lost in A3 enzymes unable to restrict HIV, we studied A3C. Human A3C is not able to restrict HIV, in comparison to the more active gorilla and chimpanzee A3C orthologs that can restrict HIV, however an explanation for this difference was lacking. A polymorphism, S188I, in human A3C, which is found in less than 3% of the global population lead...

show abstract

Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage

Cited by 27 publications

References 55 publications

APOBEC3-mediated restriction of RNA virus replication

APOBEC3-mediated restriction of RNA virus replication

APOBEC3s: DNA‐editing human cytidine deaminases

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

Contact Info

Product

Resources

About