Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells

Laboratory of Genetics, Salk Institute, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2011; 108(51):20382-7. DOI: 10.1073/pnas.1100273108
Source: PubMed


Long interspersed element-1 (L1) retrotransposons compose ∼20% of the mammalian genome, and ongoing L1 retrotransposition events can impact genetic diversity by various mechanisms. Previous studies have demonstrated that endogenous L1 retrotransposition can occur in the germ line and during early embryonic development. In addition, recent data indicate that engineered human L1s can undergo somatic retrotransposition in human neural progenitor cells and that an increase in human-specific L1 DNA content can be detected in the brains of normal controls, as well as in Rett syndrome patients. Here, we demonstrate an increase in the retrotransposition efficiency of engineered human L1s in cells that lack or contain severely reduced levels of ataxia telangiectasia mutated, a serine/threonine kinase involved in DNA damage signaling and neurodegenerative disease. We demonstrate that the increase in L1 retrotransposition in ataxia telangiectasia mutated-deficient cells most likely occurs by conventional target-site primed reverse transcription and generate either longer, or perhaps more, L1 retrotransposition events per cell. Finally, we provide evidence suggesting an increase in human-specific L1 DNA copy number in postmortem brain tissue derived from ataxia telangiectasia patients compared with healthy controls. Together, these data suggest that cellular proteins involved in the DNA damage response may modulate L1 retrotransposition.

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Available from: Angela Macia, Sep 30, 2015
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    • "translationalmousemodels(Muotrietal.,2010),andataxia telangiectasia(Coufaletal.,2011).EstimatesbasedonqPCR copynumberassaysindicated80–800newinsertionsineach hippocampalneuron(Coufaletal.,2009),whereasnewer single-cellsequencingdatasuggestarateofuniquesomatic "
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    Frontiers in Behavioral Neuroscience 05/2015; 9. DOI:10.3389/fnbeh.2015.00120 · 3.27 Impact Factor
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    • "The mice knockouts of ligase IV or XRCC4, proteins responsible for the nonhomogenous end-joining form of DNA repair, produce syndromes that lead to dysgenesis and death in the central nervous system followed by death of the embryo.41–43 Although the precise mechanism of neurodegeneration remains unknown, since pronounced neurodegeneration and ataxia are not observed in ATM null mice, it is thought that mitochondrial defects, accumulation of reactive oxygen species, transposon mobilization, innate immune responses, regulation of apoptosis, or specific repair pathway defects may contribute to triggering neuronal cell death.40,44,45 In rapidly dividing tissues, like bone marrow, cells with defective DNA repair undergo apoptosis and are replaced by nondefective ones, but in the central nervous system with terminally differentiated neurons that are highly active cells with, very restricted, if any, regeneration potential cannot be so replaced after apoptosis. "
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    ABSTRACT: Ataxia-telangiectasia (A-T) is an autosomal recessive multi-system disorder caused by mutation in the ataxia-telangiectasia mutated gene (ATM). ATM is a large serine/threonine protein kinase, a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) family whose best-studied function is as master controller of signal transduction for the DNA damage response (DDR) in the event of double strand breaks (DSBs). The DDR rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell-cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence. DSBs can be generated by exposure to ionizing radiation (IR) or various chemical compounds, such as topoisomerase inhibitors, or can be part of programmed generation and repair of DSBs via cellular enzymes needed for the generation of the antibody repertoire as well as the maturation of germ cells. AT patients have immunodeficiency, and are sterile with gonadal dysgenesis as a result of defect in meiotic recombination. In the cells of nervous system ATM has additional role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Moderate levels of ATM are associated with prolonged lifespan through resistance to oxidative stress. ATM inhibitors are being viewed as potential radiosensitizers as part of cancer radiotherapy. Though there is no cure for the disease at present, glucocorticoids have been shown to induce alternate splicing site in the gene for ATM partly restoring its activity, but their most effective timing in the disease natural history is not yet known. Gene therapy is promising but large size of the gene makes it technically difficult to be delivered across the blood-brain barrier at present. As of now, apart from glucocorticoids, use of histone deacetylase inhibitors/EZH2 to minimize effect of the absence of ATM, looks more promising.
    The Application of Clinical Genetics 09/2014; 7:159-67. DOI:10.2147/TACG.S35759
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    • "Since LINE element retrotransposition proceeds by target-site primed reverse transcription (TPRT), which requires element-encoded endonuclease (EN) and reverse transcriptase (RT) activities (Luan et al., 1993; Feng et al., 1996), we investigated whether A3A specifically interferes with L1 EN or L1 RT activity. In addition to canonical TPRT, human L1s can mobilize by an alternative, endonucleaseindependent retrotransposition mechanism (ENi) in cells that lack p53 activity and are defective for components of the non-homologous end joining (NHEJ) DNA repair machinery (Morrish et al., 2002, 2007; Coufal et al., 2011). We reasoned that if A3A specifically inhibits L1 EN activity, ENi L1 retrotransposition events should escape A3A inhibition. "
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