APOBEC3A deaminates transiently exposed single-strand DNA during LINE-1 retrotransposition

Richardson, Sandra R.; Narvaiza, Iñigo; Planegger, Randy A; Weitzman, Matthew D.; Moran, John V.

doi:10.7554/elife.02008

Cited by 120 publications

(151 citation statements)

References 71 publications

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“…While A3G resides in the cytoplasm, where it becomes incorporated into retroviral virions, A3 enzymes such as A3A, A3B and A3C enter the nucleus, where they are able to target other pathogens including human papillomaviruses (HPV) and also retrotransposons; mobile elements within the genome which appear to be targeted by multiple APOBEC enzymes via a variety of mechanisms [12][13][14][15][16][17][18][19]. With nuclear localization however, comes the risk of off-target activity against host genomic DNA and the potential for mutagenesis.…”

Section: Deoxycytidine Deamination In Innate Immunity and Somatic Mutmentioning

confidence: 99%

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APOBEC3 genes: retroviral restriction factors to cancer drivers

Henderson

Fenton

2015

Trends in Molecular Medicine

103

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Abstract:The APOBEC3 cytosine deaminases play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Now recent advances in cancer genomics together with biochemical characterization of the APOBEC3 enzymes have implicated at least two family members in somatic mutagenesis during tumor development. Here we review the evidence linking these enzymes to carcinogenesis and highlight key questions, including the potential mechanisms that misdirect APOBEC3 activity to the host genome, the links to viral infection, and the association between a common APOBEC3 polymorphism and cancer risk. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationHenderson and Fenton: highlights AbstractThe APOBEC3 cytosine deaminases play key roles in innate immunity through their

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Section: Deoxycytidine Deamination In Innate Immunity and Somatic Mutmentioning

confidence: 99%

“…It is possible that these cytoplasmic A3s inhibit retroelements in an indirect manner distinct from the deamination-based inhibition by A3A [16,17]. Again, the close similarity between the A3s is an obstacle to study of their subcellular localization.…”

Section: A3 Expression and Stimulationmentioning

confidence: 99%

APOBEC3 genes: retroviral restriction factors to cancer drivers

Henderson

Fenton

2015

Trends in Molecular Medicine

103

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“…It is also evident that small RNAs play an important role in the suppression of L1 retrotransposition in the mammalian germline (Girard et al 2006;Watanabe et al 2006;Yang and Kazazian Jr. 2006;Kuramochi-Miyagawa et al 2008). Finally the APOBEC3 family of RNA editing proteins have been shown to inhibit L1 activity in human cells (Bogerd et al 2006;Chen et al 2006;Muckenfuss et al 2006;Richardson et al 2014). However, despite all these defense mechanisms, L1s are still active in some tissues.…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

et al. 2018

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Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development.

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confidence: 99%

“…One example is the APOBEC family of proteins that are cytidine deaminase and inactivate viral or LINE-1 DNA by introducing lethal mutations. [19][20][21][22][23] An RNA helicase MOV10 inhibits retrotransposition of LINE-1 by associating with LINE-1 RNP and diminishing LINE-1 RNA level. [24][25][26] A recent study by Goodier et al tested a panel of viral restriction factors and showed that many of them, including BST-2, ISG20, MAVS, Mx2 and ZAP, strongly reduce LINE-1 activity.…”

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confidence: 99%

Stress out the LINEs

Liang

Guo

2015

Mobile Genetic Elements

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Occupying 17% of human genome, the mobile long interspersed element 1 (LINE-1 or L1) continues to modulate the landscape of our genome by inserting into new loci and, as a result, causing sporadic diseases. It is not surprising that human cells have evolved a battery of mechanisms to control and limit the activity of LINE-1. Our recent study unravels such a mechanism that is imposed by the stress granule pathway. This mechanism functions by sequestering the LINE-1 RNA-protein complex within the cytoplasmic stress granules and thus inhibiting the nuclear import of LINE-1 RNA and its subsequent reverse transcription and integration into cellular DNA. Conditions that promote stress granule formation, such as expression of the SAMHD1 protein, further reduce LINE-1 retrotransposition.KEYWORDS host restriction; LINE-1; SAMHD1; stress granule; retrotransposition Approximately 45% of human genome has been derived from transposable elements. 1 These include DNA transposons, long terminal repeat (LTR) retrotransposons (also called endogenous retroviruses), and non-LTR retrotransposons. Long interspersed element 1 (LINE-1) belongs to non-LTR retrotransposons and comprises »17% of human genome. 1 Compared to the other transposons that have mostly become inactive, approximately 100 copies of LINE-1 are still active. 2 Retrotransposition of these LINE-1s is associated with nearly 100 human diseases. 3 LINE-1 encodes two proteins called ORF1 and ORF2. ORF1 is an RNA-binding protein and associates with LINE-1 RNA. [4][5][6][7] ORF2 is an enzyme that has endonuclease and reverse transcriptase activities. 8,9 ORF1, ORF2 and LINE-1 RNA together form an RNP complex that needs to enter the nucleus where LINE-1 RNA is reverse transcribed and integrated into cellular DNA. [10][11][12] Humans have survived LINE-1 invasion and amplification over millions of years thanks to the evolution of a battery of mechanisms that control LINE-1 activity. Some of these mechanisms begin to be unraveled as a result of intensive research in the past couple of decades. One such mechanism is suppression of LINE-1 transcription by methylating LINE-1 DNA. [13][14][15] In support of this mechanism, knockdown or knockout genes that are involved in DNA methylation leads to increase in the activities of LINE-1 and other transposons. 13 In the course of embryonic development there are a couple of waves of DNA demythlyation. DNA demethylation inevitably activates LINE-1 RNA expression. 16 To control retrotransposition of LINE-1 and other transposable elements, primordial germ cells (PGCs) are equipped with the piRNA machinery to inactivate LINE-1 so as to protect the integrity of genome DNA in germ cells. 17,18 Recent studies have revealed that cells have a rich layer of mechanisms that check LINE-1 activity at the post-transcription stage. Many of these mechanisms involve cellular factors that have been shown to restrict viral infections. One example is the APOBEC family of proteins that are cytidine deaminase and inactivate viral or LINE-1 DNA by intro...

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APOBEC3A deaminates transiently exposed single-strand DNA during LINE-1 retrotransposition

Cited by 120 publications

References 71 publications

APOBEC3 genes: retroviral restriction factors to cancer drivers

APOBEC3 genes: retroviral restriction factors to cancer drivers

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

Stress out the LINEs

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