Mobile DNA in Health and Disease

Kazazian, Haig H.; Moran, John V.

doi:10.1056/nejmra1510092

Cited by 365 publications

(368 citation statements)

References 98 publications

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“…Inspired by previous studies that employ a disrupting intron to monitor mobilization of retrotransposons (Boeke et al, 1985; Jensen and Heidmann, 1991; Moran et al, 1996), which represent the majority of transposons in the animal genome (Chuong et al, 2017; Kazazian and Moran, 2017), we constructed a reporter whereby eGFP signal is only produced after retrotransposition (Figure 1A and S1A). In essence, the eGFP reporter, which is placed at the 3′ end of the transposon in the antisense orientation, is disrupted by an intron in the same orientation as the transposon (Figure 1A and S1A).…”

Section: Resultsmentioning

confidence: 99%

“…Supporting this idea, the LINE1 transposons from mouse genome indeed show differential accumulation of the Orf1p proteins among otherwise genetically identical cells within a cyst (Malki et al, 2014). Additionally, accumulating evidence indicates that retrotransposon activation contributes to mammalian embryogenesis, neurogenesis, and tumorigenesis (Burns, 2017; Erwin et al, 2016; Grow et al, 2015; Kazazian and Moran, 2017). Perhaps these endogenous retroviruses drive development or promote disease also by taking their preferential rides.…”

Section: Discussionmentioning

confidence: 99%

“…As the most abundant residents in the genomes of nearly all eukaryotes, transposons represent a potential source of genome instability (Chuong et al, 2017; Kazazian and Moran, 2017). Although the hosts have evolved multiple mechanisms to suppress transposable elements, “leaky” mobilizations that cause mutations and diseases still occur (Chuong et al, 2017; Kazazian and Moran, 2017; Weick and Miska, 2014; Yang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Hijacking Oogenesis Enables Massive Propagation of LINE and Retroviral Transposons

Wang

Dou

Moon

et al. 2018

Cell

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Although animals have evolved multiple mechanisms to suppress transposons, "leaky" mobilizations that cause mutations and diseases still occur. This suggests that transposons employ specific tactics to accomplish robust propagation. By directly tracking mobilization, we show that, during a short and specific time window of oogenesis, retrotransposons achieve massive amplification via a cell-type-specific targeting strategy. Retrotransposons rarely mobilize in undifferentiated germline stem cells. However, as oogenesis proceeds, they utilize supporting nurse cells-which are highly polyploid and eventually undergo apoptosis-as factories to massively manufacture invading products. Moreover, retrotransposons rarely integrate into nurse cells themselves but, instead, via microtubule-mediated transport, they preferentially target the DNA of the interconnected oocytes. Blocking microtubule-dependent intercellular transport from nurse cells significantly alleviates damage to the oocyte genome. Our data reveal that parasitic genomic elements can efficiently hijack a host developmental process to propagate robustly, thereby driving evolutionary change and causing disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hijacking Oogenesis Enables Massive Propagation of LINE and Retroviral Transposons

Wang

Dou

Moon

et al. 2018

Cell

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“…Genome-wide binding analyses of TRIM28 in human ESCs and primary human T lymphocytes [65, 66] indicate that KRAB-ZFPs can not only suppress LTR transposons, but also non-retroviral transposable elements (for a summary of these see [67]) including LINE-1 and several groups of SINE-VNTR- Alu (SVA) families. ZNF91 and ZNF93, two human-specific KRAB-ZFPs, directly target and silence SVA and LINE-1 (L1), respectively [68].…”

Section: Biological Functions Of Krab Zinc Finger Proteinsmentioning

confidence: 99%

The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution

2017

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Kruppel-associated box zinc finger proteins (KRAB-ZFPs) make up the largest family of transcription factors in humans. These proteins emerged in the last common ancestor of coelacanth and tetrapods and have expanded and diversified in the mammalian lineage. Although their mechanism of transcriptional repression has been well studied for over a decade, the DNA binding activities and the biological function of these proteins has been largely unexplored. Recent large scale ChIP-seq studies and loss-of-function experiments have revealed that KRAB-ZFPs play a major role in the recognition and transcriptional silencing of transposable elements (TEs), consistent with an “arms race model” of KRAB-ZFP evolution against invading TEs. However, this model is insufficient to explain the evolution of many KRAB-ZFPs that appear to domesticate TEs for novel host functions. We highlight some of the mammalian regulatory innovations driven by specific KRAB-ZFPs, including genomic imprinting, meiotic recombination hotspot choice, and placental growth.

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“…Actually, mutagenic L1 retrotransposition events have been implicated in more than 100 genetic diseases (Kazazian Jr et al 1988;Kazazian Jr and Moran 2017;Beck et al 2011;Kaer and Speek 2013;Hancks and Kazazian Jr 2016). Moreover, somatic L1 retrotransposition may play a role in tumorigenesis (reviewed in Burns 2017).…”

Section: Transposable Elements In the Human Genomementioning

confidence: 99%

Post-transcriptional regulation of LINE-1 retrotransposition by AID/APOBEC and ADAR deaminases

et al. 2018

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Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our genome. Even though most of the human L1 sequences are inactive, a limited number of copies per individual retain the ability to mobilize by a process termed retrotransposition. The ongoing L1 retrotransposition may result in insertional mutagenesis that could lead to negative consequences such as genetic disease and cancer. For this reason, cells have evolved several mechanisms of defense to restrict L1 activity. Among them, a critical role for cellular deaminases [activation-induced deaminase (AID)/apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) and adenosine deaminases that act on RNA (ADAR) enzymes] has emerged. The majority of the AID/ APOBEC family of proteins are responsible for the deamination of cytosine to uracil (C-to-U editing) within DNA and RNA targets. The ADARs convert adenosine bases to inosines (A-to-I editing) within doublestranded RNA (dsRNA) targets. This review will discuss the current understanding of the regulation of LINE-1 retrotransposition mediated by these enzymes.

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Mobile DNA in Health and Disease

Cited by 365 publications

References 98 publications

Hijacking Oogenesis Enables Massive Propagation of LINE and Retroviral Transposons

Hijacking Oogenesis Enables Massive Propagation of LINE and Retroviral Transposons

The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution

Post-transcriptional regulation of LINE-1 retrotransposition by AID/APOBEC and ADAR deaminases

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