The APOBEC Protein Family: United by Structure, Divergent in Function

Salter, Jason D.; Bennett, Ryan P.; Smith, Harold C.

doi:10.1016/j.tibs.2016.05.001

Cited by 333 publications

(373 citation statements)

References 144 publications

(189 reference statements)

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“…APOBEC and AID enzymes modify cytidine in either mRNA or single-stranded (ss) DNA to form uracil [5][6][7]. Other members have also been identified, including APOBEC2 and APOBEC4, though they do not have demonstrated catalytic activity [3,8,9].…”

Section: Apobec Family Of Enzymesmentioning

confidence: 99%

“…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%

“…The APOBEC family of enzymes in humans has 12 members and is comprised of RNA and DNA cytidine deaminases [5]. The enzymes are named after APOBEC1, the first family member discovered, that edits the mRNA of apolipoprotein B in the intestine by converting cytosine to uracil and forming a stop codon [5].…”

Section: Introductionmentioning

confidence: 99%

“…The enzymes are named after APOBEC1, the first family member discovered, that edits the mRNA of apolipoprotein B in the intestine by converting cytosine to uracil and forming a stop codon [5]. Other family members with demonstrated deaminase activity have roles in immunity.…”

Section: Introductionmentioning

confidence: 99%

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Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

2018

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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...

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Section: Apobec Family Of Enzymesmentioning

confidence: 99%

Section: Apobec Family Of Enzymesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

2018

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“…20,34,[39][40][41][42][43] These studies have concluded that A3B prefers DNA substrates but can bind and catalyze other substrates with significantly lower activity. 44 DNA and RNA differ in structure by only one hydroxyl group (at the C2' position), which is enough to change the backbone sugar ring pucker from C2' endo (for DNA) to C3' endo (for RNA). It is suspected that this difference in conformational preference is a contributing factor for A3B's selectivity for DNA over RNA, but the exact mechanism is not known.…”

Section: Introductionmentioning

confidence: 99%

Determinants of Substrate Specificity in APOBEC3B

Wagner

Demir²,

Carpenter³

et al. 2018

Preprint

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APOBEC3B (A3B) is a newly discovered driver of mutation in many cancers. We use computational tools to revert a recent crystal structure of an A3B construct to its native sequence, and run molecular dynamics simulations to study its underlying dynamics and substrate recognition mechanisms. The A3B oligonucleotide substrate simulations show a series of dynamic substrate protein contacts that correlate with previous work on A3B substrate selectivity. A second series of simulations in which the target cytosine nucleotide was computationally mutated from a deoxyribose to a ribose showed a change in sugar ring pucker, leading to a rearrangement of the binding site and revealing a potential intermediate in the binding pathway. Finally, apo simulations of A3B beginning in the open state experience a rapid and consistent closure of the binding site, reaching a conformation incompatible with substrate binding. These simulations agree with previous experimental studies, and we report the atomistic details of these events to further therapeutic studies on A3B. IntroductionThe APOBEC3 (A3) family of cytidine deaminases is a recently discovered endogenous source of mutation in cancer. 1,2 Previously, A3 proteins were studied in the context of their interactions with viruses and efforts were undertaken to discover small molecules that modulate the mutational activities of the virally restrictive APOBEC3G enzyme. 3,4 Recent studies have linked cancer progression and recurrence to A3 activity. 5-9 A3 proteins have specific substrate sequence preferences, and analyses of some cancer genomes have shown an enrichment of A3 mutation signatures. [10][11][12][13][14][15] Recent evidence suggests that APOBEC3B (A3B) is an important driver of tumor progression in the A3 family. 16,17

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Atomic Force Microscopy Methods forDNAAnalysis

Lyubchenko¹

2019

Encyclopedia of Analytical Chemistry

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Applications of atomic force microscopy (AFM) to imaging of DNA with various structures, topologies, and complexes with proteins are reviewed. The emphasis is given to methods utilizing chemical functionalization of mica, enabling AFM visualization of different DNA structures. Special attention is given to the ability of AFM to image the dynamics of DNA at the nanoscale. The capabilities of time‐lapse AFM in aqueous solutions are illustrated by imaging of dynamic processes as transitions of local alternative structures (transition of DNA between H and B forms). The application of AFM to studies of protein–DNA complexes is illustrated by a few examples of imaging site‐specific complexes, as well as systems such as chromatin. The time‐lapse AFM studies of protein–DNA complexes including very recent advances with the use of high‐speed AFM are reviewed.

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The APOBEC Protein Family: United by Structure, Divergent in Function

Cited by 333 publications

References 144 publications

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

Determinants of Substrate Specificity in APOBEC3B

Atomic Force Microscopy Methods forDNAAnalysis

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