Mutations in<i>String/CDC25</i>inhibit cell cycle re-entry and neurodegeneration in a<i>Drosophila</i>model of Ataxia telangiectasia

Rimkus, Stacey A.; Katzenberger, Rebeccah J.; Trinh, Anthony T.; Dodson, Gerald E.; Tibbetts, Randal S.; Wassarman, David A.

doi:10.1101/gad.1639608

Cited by 41 publications

(34 citation statements)

References 97 publications

(94 reference statements)

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“…dATM mutants also show similar phenotypes associated with ATM patients such as neurodegeneration 10,11 , abnormal telomere protection 12,13 , increased apoptosis and chromosome fragmentation by DSB repair defects 10,11,[13][14][15] . Additionally, dATM participates in silencing the expression of genes adjacent to telomere ends (telomere position effect) 16,17 and in alternative splicing of pre-messenger RNA 18 .…”

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confidence: 81%

“…Additionally, dATM participates in silencing the expression of genes adjacent to telomere ends (telomere position effect) 16,17 and in alternative splicing of pre-messenger RNA 18 . In Drosophila, although genetic evidence suggests that dATM is positively regulated by MRN 19 and negatively by histone deacetylase (RPD3) 10 , little is known how dATM is activated biochemically.…”

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confidence: 99%

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TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster

Hong

Choi

2013

Nat Commun

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Translationally controlled tumour protein (TCTP) is implicated in growth regulation and cancer. Recently, human TCTP has been suggested to play a role in the DNA damage response by forming a complex with ataxia telangiectasia-mutated (ATM) kinase . However, the exact nature of this interaction and its roles in vivo remained unclear. Here, we utilize Drosophila as an animal model to study the nuclear function of Drosophila TCTP (dTCTP). dTCTP mutants show increased radiation sensitivity during development as well as strong genetic interaction with dATM mutations, resulting in severe defects in developmental timing, organ size and chromosome stability. We identify Drosophila ATM (dATM) as a direct binding partner of dTCTP and describe a mechanistic basis for dATM activation by dTCTP. Altogether, this study provides the first in vivo evidence for direct modulation of dATM activity by dTCTP in the control of genome stability and organ development.

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confidence: 81%

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confidence: 99%

TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster

Hong

Choi

2013

Nat Commun

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“…Fluorescence microscopy was performed using a Zeiss Axiovert 200M fluorescence microscope. Transmission electron microscopy (TEM) of ommatidia was performed as described previously (24).…”

Section: Methodsmentioning

confidence: 99%

Ubiquilin Modifies TDP-43 Toxicity in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

Hanson¹,

Kim

Wassarman

et al. 2010

Journal of Biological Chemistry

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“…Since ATM is essential in flies, we have used a temperature-sensitive ATM allele (ATM 8 ) and ATM RNA interference (RNAi) to conditionally inactivate ATM (Silva et al 2004;Rimkus et al 2008;Pedersen et al 2010;. ATM 8 homozygous flies cultured at 25°are pupal lethal but when cultured at 18°they are viable (Silva et al 2004).…”

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confidence: 99%

The Innate Immune Response Transcription Factor Relish Is Necessary for Neurodegeneration in aDrosophilaModel of Ataxia-Telangiectasia

2013

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Neurodegeneration is a hallmark of the human disease ataxia-telangiectasia (A-T) that is caused by mutation of the A-T mutated (ATM) gene. We have analyzed Drosophila melanogaster ATM mutants to determine the molecular mechanisms underlying neurodegeneration in A-T. Previously, we found that ATM mutants upregulate the expression of innate immune response (IIR) genes and undergo neurodegeneration in the central nervous system. Here, we present evidence that activation of the IIR is a cause of neurodegeneration in ATM mutants. Three lines of evidence indicate that ATM mutations cause neurodegeneration by activating the Nuclear Factor-kB (NF-kB) transcription factor Relish, a key regulator of the Immune deficiency (Imd) IIR signaling pathway. First, the level of upregulation of IIR genes, including Relish target genes, was directly correlated with the level of neurodegeneration in ATM mutants. Second, Relish mutations inhibited upregulation of IIR genes and neurodegeneration in ATM mutants. Third, overexpression of constitutively active Relish in glial cells activated the IIR and caused neurodegeneration. In contrast, we found that Imd and Dif mutations did not affect neurodegeneration in ATM mutants. Imd encodes an activator of Relish in the response to gram-negative bacteria, and Dif encodes an immune responsive NF-kB transcription factor in the Toll signaling pathway. These data indicate that the signal that causes neurodegeneration in ATM mutants activates a specific NF-kB protein and does so through an unknown activator. In summary, these findings suggest that neurodegeneration in human A-T is caused by activation of a specific NF-kB protein in glial cells.

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Mutations inString/CDC25inhibit cell cycle re-entry and neurodegeneration in aDrosophilamodel of Ataxia telangiectasia

Abstract: Mutations in ATM (Ataxia telangiectasia mutated) result in Ataxia telangiectasia (A-T), a disorder[Keywords: Drosophila; neurodegeneration; Ataxia telangiectasia; ATM; cell cycle; HDAC] Supplemental material is available at http://www.genesdev.org.

Cited by 41 publications

References 97 publications

TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster

TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster

Ubiquilin Modifies TDP-43 Toxicity in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

The Innate Immune Response Transcription Factor Relish Is Necessary for Neurodegeneration in aDrosophilaModel of Ataxia-Telangiectasia

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