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: 9.81). 12/2011; 108(51):20382-7. DOI: 10.1073/pnas.1100273108
Source: PubMed

ABSTRACT 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, Jul 28, 2015
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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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    • "Pluripotent human embryonic stem cells (hESCs), which can be differentiated into neural progenitors and mature neurons and astrocytes, provide another powerful model system to assess the effects of loss or inactivation of ATM. Also for these studies, ATM has either been stably knockdown by transducing hESCs with lentiviruses harbouring shRNA against ATM [27] [35], or chemically inhibited with KU-55933 [28]. Interestingly, neuronal models of A-T based on the use of patients' tissues are currently being developed. "
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    • "Unlike the immune system or germline, there are no known programs of DNA breakage and repair that would provide an obvious trigger for cell death. It has been speculated that mitochondrial defects, the accumulation of ROS, transposon mobilization, innate immune responses, the regulation of apoptosis or specific repair pathway defects may contribute to triggering neuronal cell death (Coufal et al., 2011; McKinnon, 2012; Petersen et al., 2012; Valentin-Vega and Kastan, 2012). One of the central pathologies associated with A-T is neurodegeneration , characterized by cerebellar atrophy and the loss of Purkinje and granule cells and subsequent ataxia. "
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