Structure-Function Analyses Point to a Polynucleotide-Accommodating Groove Essential for APOBEC3A Restriction Activities

Bulliard, Yannick; Narvaiza, Iñigo; Bertero, Alessandro; Peddi, Shyam; Röhrig, Ute F.; Ortiz, Millán; Zoete, Vincent; Castro-Díaz, Nataly; Turelli, Priscilla; Telenti, Amalio; Michielin, Olivier; Weitzman, Matthew D.; Trono, Didier

doi:10.1128/jvi.01651-10

Cited by 71 publications

(90 citation statements)

References 59 publications

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“…Since this history of selection apparently predates the emergence of primate lentiviruses, and the constant rate of selection is inconsistent with the episodic selective pressure that would be applied by an infectious extracellular pathogen, these findings imply that APOBEC3 genes are in conflict with a constant and ancient threat to genomic stability, such as that posed by L1 or other endogenous retrotransposable elements (55). The data from a number of studies support that the overexpression of APOBEC3 proteins in cell lines suppress the retrotransposition of engineered L1 elements (41,42,(56)(57)(58)(59)(60). Different APOBEC3 members exert different levels of suppression with APOBEC3A, -3B, and -3F consistently exhibiting potent effects, whereas APOBEC3G exhibited modest or no activity in the majority of these studies.…”

Section: In Primary Cd4mentioning

confidence: 69%

LINE-1 Retrotransposable Element DNA Accumulates in HIV-1-Infected Cells

Jones

Song

et al. 2013

J Virol

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Type 1 long-interspersed nuclear elements (L1s) are autonomous retrotransposable elements that retain the potential for activity in the human genome but are suppressed by host factors. Retrotransposition of L1s into chromosomal DNA can lead to genomic instability, whereas reverse transcription of L1 in the cytosol has the potential to activate innate immune sensors. We hypothesized that HIV-1 infection would compromise cellular control of L1 elements, resulting in the induction of retrotransposition events. Here, we show that HIV-1 infection enhances L1 retrotransposition in Jurkat cells in a Vif-and Vpr-dependent manner. In primary CD4؉ cells, HIV-1 infection results in the accumulation of L1 DNA, at least the majority of which is extrachromosomal. These data expose an unrecognized interaction between HIV-1 and endogenous retrotransposable elements, which may have implications for the innate immune response to HIV-1 infection, as well as for HIV-1-induced genomic instability and cytopathicity. L 1 element DNA sequences comprise approximately 17% of the human genome (1, 2). Although the bulk of these sequences are in the form of short 5= truncated insertions, an estimated 100 full-length intact elements are present (3, 4). These intact L1 elements represent the only retrotransposons encoded by the human genome known to be capable of autonomous replication (4-7). Full-length L1 elements are ϳ6 kb in length, comprising a 5=-untranslated region (5=UTR) two open reading frames (ORF1 and ORF2) and a 3=UTR ending in a poly(A) tail (8). ORF1 encodes a 40-kDa protein with RNA chaperone activity, while ORF2 encodes a 150-kDa protein which possesses the reverse transcriptase (RT) and endonuclease functions required for retrotransposition (6,(9)(10)(11)(12)(13)(14)(15)(16)(17). Productive retrotransposition is thought to occur by a mechanism termed target-primed reverse transcription (TPRT), where reverse transcription is primed against genomic DNA at the insertion site and thus occurs in concert with integration (18)(19)(20).Several cases of genetic disease have been traced to gene disruptions caused by L1 retrotransposition events in germ line cells, and L1 retrotransposition in somatic cells has been implicated in oncogenesis and cancer progression (21-26). L1 retrotransposition may also play a role in normal physiology. Previous studies have demonstrated the ability for tagged, engineered L1 elements to retrotranspose in neural progenitor cells, and this, supported by quantitative PCR (qPCR) data showing elevated copy numbers of L1 elements in the adult human brain, has led to the suggestion that L1 retrotransposition may play a role in the generation of neuronal somatic mosaicism (27, 28). The vast amount of L1 element sequence fixed in the human genome has, however, presented a technical challenge to the isolation of novel endogenous L1 genomic insertions in somatic cells.Although TPRT appears to be the primary mechanism by which novel genomic L1 insertions are generated, there is considerable evidence that cytosolic...

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Section: In Primary Cd4mentioning

confidence: 69%

LINE-1 Retrotransposable Element DNA Accumulates in HIV-1-Infected Cells

Jones

Song

et al. 2013

J Virol

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“…[27][28][29] Third, researchers have demonstrated that APOBEC3A and other family members have the potential to mediate the clearance of foreign DNA through a deamination-dependent mechanism. [27,30,31] Recent work has also indicated that there are regions of the genome that appear more susceptible to mutation than others. Specifically, late-replicating and heterochromatic regions of the genome appear enriched for mutations when compared to early replicating and euchromatic DNA, respectively.…”

Section: The Apobec Familymentioning

confidence: 99%

APOBEC3B: Pathological consequences of an innate immune DNA mutator

Burns¹,

Leonard²,

Harris³

2015

Biomed J

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Cancer is a disease that results from alterations in the cellular genome. Several recent studies have identified mutational signatures that implicate a variety of mutagenic processes in cancer, a major one of which is explained by the enzymatic activity of the DNA cytosine deaminase, APOBEC3B. As a deaminase, APOBEC3B converts cytosines to uracils in single-stranded DNA. Failure to properly repair these uracil lesions can result in a diverse array of mutations. For instance, DNA uracils can template the insertion of complementary adenines leading to C-to-T transition mutations. DNA uracils can also be converted into abasic sites that, depending upon the DNA polymerase recruited to bypass this lesion in the template strand, can lead to adenine insertion and C-to-T mutations as well as cytosine insertion and C-to-G transversion mutations. Finally, DNA uracils can also be converted into DNA breaks that may precipitate some types of larger chromosomal aberrations observed in cancer. These studies cumulatively demonstrate that APOBEC3B is a major source of genetic heterogeneity in several human cancers and, as such, this enzyme may prove to be a critical diagnostic and therapeutic target. (Biomed J 2015;38:102-110)

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“…Although viral DNA integration is an important step in HPV-induced carcinogenesis (24,25), a mechanism of HPV integration remains unknown. A3s can also target DNA viruses that do not use reverse transcription in their replication cycle, including TT virus, adeno-associated virus (AAV), herpes simplex virus 1 (HSV-1), and Epstein-Barr virus (26)(27)(28)(29)(30) (32), raising a concern about whether the observed hypermutation in the transfected HPV DNA truly reflects HPV pathophysiology.…”

mentioning

confidence: 99%

APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

Wang

Wakae

Kitamura

et al. 2014

J Virol

101

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A polipoprotein B mRNA-editing catalytic polypeptide (APOBEC) proteins are a family of proteins that share cytidine deaminase activity of DNA and RNA. In humans, the APOBEC family is composed of at least 11 members, including activation-induced cytidine deaminase (AID) and APOBEC1, -2, -3A, -3B, -3C, -3DE, -3F, -3G, -3H, and -4 (1, 2). AID introduces cytidine (C)-to-uracil (U) conversion in immunoglobulin (Ig) genes, a step that is further catalyzed by downstream DNA repair machineries, including base excision repair (BER), mismatch repair, and nonhomologous end-joining repair, to trigger somatic hypermutation, class switch recombination, gene conversion, and chromosomal translocation (3-6). AID also introduces mutations in non-Ig gene loci, such as c-Myc and Bcl-6, although less frequently than in Ig genes (3, 7). Recent studies have suggested that APOBEC3 protein (A3) deaminase activity is responsible for a novel type of mutations called kataegis in multiple human cancers, including cancers of the bladder, cervix, lung, head and neck, and breast (8-13).A3s are antiviral factors against viruses and transposable elements that use reverse transcription during their life cycle (1, 2, 14-16). The antiviral functions of A3s have been extensively studied for human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). APOBEC3G (A3G) physically associates with viral RNP complexes, including viral genomic RNA, gag protein (in the case of HIV-1), and P and core protein (in the case of HBV), and is encapsidated into a nucleocapsid, thereby inhibiting reverse transcription in infected cells (2,14,17). Moreover, A3G-induced hypermutation in viral DNA leads to inhibition of HIV-1 replication by either BER-mediated DNA degradation or accumulation of destructive mutations in the viral genome (16,(18)(19)(20). How C-to-U conversion in cellular or viral DNA is converted into different genetic alterations (hypermutation, recombination, and DNA degradation) remains unknown.Human papillomaviruses (HPVs) are small double-stranded DNA viruses infecting epithelial cells. A subset of mucosal HPVs is recognized as a causative agent of cervical cancer (21, 22), among which HPV16 accounts for at least 50% of cervical cancer cases worldwide (23). The HPV16 genome is a 7.9-kb closed circular DNA and is composed of at least 8 open reading frames (E1, E2, E4, E5, E6, E7, L1, and L2) as well as the noncoding long control region (LCR). LCR contains the replication origin and the P 97 promoter responsible for transcription of the E6 and E7 genes. E6 and E7 are viral oncoproteins that degrade p53 and retinoblastoma proteins, respectively, and their enhanced expression is required for cellular transformation (22). In its normal life cycle, HPV16 infects the basal cells of cervical epithelia and establishes their genomes as extrachromosomal episomes. In invasive cervical cancer, however, the viral DNA is frequently integrated into the host chromosome, which generally leads to constitutive expression of E6 and E7. The viral DNA integrat...

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Structure-Function Analyses Point to a Polynucleotide-Accommodating Groove Essential for APOBEC3A Restriction Activities

Cited by 71 publications

References 59 publications

LINE-1 Retrotransposable Element DNA Accumulates in HIV-1-Infected Cells

LINE-1 Retrotransposable Element DNA Accumulates in HIV-1-Infected Cells

APOBEC3B: Pathological consequences of an innate immune DNA mutator

APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

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