Evidence map›Paper›PMID 28714954›Full record

ArticleNature neuroscience2017

C9orf72 expansion disrupts ATM-mediated chromosomal break repair.

Callum Walker, Saul Herranz-Martin, Evangelia Karyka, Chunyan Liao, Katherine Lewis, Waheba Elsayed, Vera Lukashchuk, Shih-Chieh Chiang, Swagat Ray, Padraig J Mulcahy and 12 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature neuroscience, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
119citing papers in PubMed, 1 pooled it
13.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

119 citing papers in PubMed, 1 synthesis or guideline pooled it, 188 citations in OpenAlex.

  1. Pooled it
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  17. NAR molecular medicine · 2024
    Article
  18. Review
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  20. Chromosomal R-loops: who R they?Biologia futura · 2024
    Review

59 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors at 2 institutions in 2 countries.

Callum WalkerSITraN and Krebs Institutes, Neurodegeneration and Genome Stability Group, University of Sheffield, Sheffield, UK.
Saul Herranz-MartinSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Evangelia KarykaSITraN and Krebs Institutes, Neurodegeneration and Genome Stability Group, University of Sheffield, Sheffield, UK.
Chunyan LiaoKrebs and Sheffield Institutes for Nucleic Acids, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield, UK.
Katherine LewisSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Waheba ElsayedKrebs and Sheffield Institutes for Nucleic Acids, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield, UK.
Vera LukashchukSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Shih-Chieh ChiangKrebs and Sheffield Institutes for Nucleic Acids, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield, UK.
Swagat RayKrebs and Sheffield Institutes for Nucleic Acids, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield, UK.
Padraig J MulcahySheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Mateusz JurgaKrebs and Sheffield Institutes for Nucleic Acids, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield, UK.
Ioannis TsagakisSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Tommaso IannittiSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Jayanth ChandranSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Ian ColdicottSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Kurt J De VosSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Mohamed K HassanKrebs and Sheffield Institutes for Nucleic Acids, Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield, UK.
Adrian HigginbottomSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Pamela J ShawSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Guillaume M HautbergueSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.ORCID http://orcid.org/0000-0002-1621-261X
Mimoun AzzouzSITraN and Krebs Institutes, Neurodegeneration and Genome Stability Group, University of Sheffield, Sheffield, UK.ORCID http://orcid.org/0000-0001-6564-5967
Sherif F El-KhamisySITraN and Krebs Institutes, Neurodegeneration and Genome Stability Group, University of Sheffield, Sheffield, UK.ORCID http://orcid.org/0000-0003-2721-7763
University of Sheffield · GBZewail City of Science and Technology · EG

Funding

European Research Council 294745Medical Research Council G1001492Medical Research Council MR/K005146/1Medical Research Council MR/M010864/1Medical Research Council MR/M013251/1Wellcome Trust
6 · The paper itself

Abstract

Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9orf72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven at least partly by genomic instability.

Indexed as

Chromosome BreakageAmyotrophic Lateral SclerosisAnimalsAtaxia Telangiectasia Mutated ProteinsC9orf72 ProteinCells, CulturedDNA RepairDNA Repeat ExpansionHEK293 CellsHumansMiceMice, Inbred C57BLProteinsRandom AllocationRatsSpinal CordAtaxia Telangiectasia Mutated ProteinsATM protein, humanC9orf72 ProteinC9orf72 protein, humanProteins

Identifiers

PMID28714954
PMCPMC5578434
OpenAlexW2734373506

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.