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

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 mutateddeficient 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.

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

“…The LINE1 promoter is active in neural precursor cells differentiating into neurons (9,42). Thus, the hippocampus, one of the two regions of the adult brain where new neurons are generated, may not be the only area with a detectable piRNA expression.…”

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

“…De novo mutations, germline mosaicism and other complexities Although this concept of somatic mosaicism has been in the literature for many years [131][132][133][134][135], it is really only recently that more people are beginning to realize that it might be much more extensive in humans than previously thought [23,[136][137][138][139][140][141][142][143][144][145][146][147][148][149]. In fact, hardly anything is truly known regarding the extent of somatic mosaicism in humans and its effect on phenotype in even well studied diseases.…”

Rétrotransposons et cellules somatiques

“…D'autres protéines sont aussi impliquées dans la répression des L1 dans les tissus somatiques, comme la protéine kinase ATM (ataxia telangiectasia mutated), jouent eux aussi un rôle clé dans la régulation des L1. Dans les cellules souches neuronales, la perte d'expression d'ATM, protéine impliquée dans la répara-tion des cassures double-brins d'ADN, entraîne, soit une augmentation du nombre d'insertions des rétrotrans-posons L1, soit l'insertion de copies plus longues [10]. De plus, ATM est aussi impliquée dans un mécanisme de méthylation des L1 par le contrôle qu'elle exerce sur la phosphorylation de la protéine BRCA1 (breast cancer 1 protein), essentielle au recrutement d'un complexe répresseur ciblant les séquences des L1 [24].…”

“…Ce mécanisme est nommé target-primed reverse transcriptase (TPRT) ( Figure 1B). Cependant, les copies de L1 nouvellement intégrées sont souvent tronquées en 5' ; ceci ne serait pas dû à la faible activité RT de l'ORF2p [7], mais plus vraisemblablement à des facteurs protéiques associés aux mécanismes de réparation de l'ADN [8][9][10]. La détection des transcrits de L1 et de la protéine ORF2p s'avère difficile dans les cellules de mammifères, même dans le contexte d'expériences de surexpression, suggérant qu'un mécanisme spécifique régule l'expression des L1 dans …”