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ATRX dysfunction induces replication defects in primary mouse cells.

ABSTRACT: The chromatin remodeling protein ATRX, which targets tandem repetitive DNA, has been shown to be required for expression of the alpha globin genes, for proliferation of a variety of cellular progenitors, for chromosome congression and for the maintenance of telomeres. Mutations in ATRX have recently been identified in tumours which maintain their telomeres by a telomerase independent pathway involving homologous recombination thought to be triggered by DNA damage. It is as yet unknown whether there is a central underlying mechanism associated with ATRX dysfunction which can explain the numerous cellular phenomena observed. There is, however, growing evidence for its role in the replication of various repetitive DNA templates which are thought to have a propensity to form secondary structures. Using a mouse knockout model we demonstrate that ATRX plays a direct role in facilitating DNA replication. Ablation of ATRX alone, although leading to a DNA damage response at telomeres, is not sufficient to trigger the alternative lengthening of telomere pathway in mouse embryonic stem cells.

SUBMITTER: Clynes D

PROVIDER: S-EPMC3961441 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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ATRX dysfunction induces replication defects in primary mouse cells.

Clynes David D Jelinska Clare C Xella Barbara B Ayyub Helena H Taylor Stephen S Mitson Matthew M Bachrati Csanád Z CZ Higgs Douglas R DR Gibbons Richard J RJ

PloS one 20140320 3

The chromatin remodeling protein ATRX, which targets tandem repetitive DNA, has been shown to be required for expression of the alpha globin genes, for proliferation of a variety of cellular progenitors, for chromosome congression and for the maintenance of telomeres. Mutations in ATRX have recently been identified in tumours which maintain their telomeres by a telomerase independent pathway involving homologous recombination thought to be triggered by DNA damage. It is as yet unknown whether th ...[more]

PMID: 24651726

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Project description:Simple Summary ATRX and DAXX mutations occur in 30–40% of pancreatic neuroendocrine tumours (PanNETs), and there are no reports in the literature of any genetically engineered mouse model (GEMM) evaluating the effect of Atrx disruption as a putative driver event on PanNET initiation. We created a novel GEMM with Atrx conditional disruption in β cells. We observed that this genetic alteration, per se, was not tumourigenic, but we reported novel roles of Atrx on endocrine function, which resulted in dysglycaemia and the exacerbation of inflammageing (increased pancreatic inflammation and hepatic steatosis). Abstract ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events.

Dataset Information

ATRX dysfunction induces replication defects in primary mouse cells.

Publications

ATRX dysfunction induces replication defects in primary mouse cells.

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