Alpha Thalassemia/Mental Retardation Syndrome X-linked Gene Product ATRX Is Required for Proper Replication Restart and Cellular Resistance to Replication Stress

Leung, Justin; Ghosal, Gargi; Wang, Wenqi; Shen, Xi; Wang, Jiadong; Li, Lei; Chen, Junjie

doi:10.1074/jbc.m112.411603

Cited by 89 publications

(109 citation statements)

References 41 publications

(23 reference statements)

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“…Ablation of ATRX in mouse myoblasts delayed their progression in S phase and led to an accumulation of DNA damage including telomere fragility [6] and similar findings were observed in a study involving neuroprogenitors [24]. In a further advance, a somatic knockout of ATRX in a colorectal cell line exhibited increased sensitivity to hydroxyurea and aphidicolin suggesting that in the absence of ATRX there is an increase in replicative stress in this cellular context [25]. Taken together with the findings presented here it is clear that ATRX has a general role in facilitating DNA replication in multiple cellular environments and that this may in part account for why loss of ATRX function results in such disparate pathologies.…”

Section: Discussionsupporting

confidence: 60%

ATRX Dysfunction Induces Replication Defects in Primary Mouse Cells

et al. 2014

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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.

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Section: Discussionsupporting

confidence: 60%

ATRX Dysfunction Induces Replication Defects in Primary Mouse Cells

et al. 2014

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“…Indeed, ATRX targets tandem repeats that preferentially form G-quadruplexes in vitro and unwinds these structures to maintain replication [87]. Consistent with this, ATRX deficiency is associated with replicative stress due to stalled replication forks [88] ( Figure 3A). As mentioned in a previous section, ATRX, together with the histone chaperone DAXX, is required for deposition of histone H3.3 into telomeres.…”

Section: Reviewmentioning

confidence: 82%

Assembly of telomeric chromatin to create ALTernative endings

O’Sullivan

Almouzni

2014

Trends in Cell Biology

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“…Other members of this class participate in DNA damage repair pathways, in particular nucleotide excision repair and double-stranded break repair (19). Previous work has shown that ATRX is recruited to sites of DNA damage (20). Thus, we hypothesized that ATRX may play a role in maintaining genetic stability in glioblastoma.…”

Section: Resultsmentioning

confidence: 99%

ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma

et al. 2016

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Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and show that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs non-homologous end joining (NHEJ) and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated, but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.

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Alpha Thalassemia/Mental Retardation Syndrome X-linked Gene Product ATRX Is Required for Proper Replication Restart and Cellular Resistance to Replication Stress

Cited by 89 publications

References 41 publications

ATRX Dysfunction Induces Replication Defects in Primary Mouse Cells

ATRX Dysfunction Induces Replication Defects in Primary Mouse Cells

Assembly of telomeric chromatin to create ALTernative endings

ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma

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