Cited by 113DNA Repair MechanismsGenomics and Chromatin DynamicsCancer-related Molecular Pathways

Identification and characterization of FUS/TLS as a new target of ATM

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Gardiner, Mary, Toth, Rachel, Vandermoere, Franck, Morrice, Nicholas A., Rouse, John·2008·Biochemical Journal

Abstract

ATM (ataxia-telangiectasia mutated), ATR (ATM- and Rad3-related) and DNA-PK (DNA-dependent protein kinase), important regulators of genome stability, belong to the PIKK (phosphoinositide 3-kinase-like kinase) family of protein kinases. In the present study, DNA-affinity chromatography was used to identify DNA-binding proteins phosphorylated by these kinases. This resulted in the identification of FUS (fused in sarcoma)/TLS (translocated in liposarcoma) as an in vitro target of the PIKKs. FUS is a member of the Ewing's sarcoma family of proteins that appears to play a role in regulating genome stability, since mice lacking FUS show chromosomal instability and defects in meiosis. The residues in FUS that are phosphorylated in vitro and in vivo were identified, and phospho-specific antibodies were generated to demonstrate that FUS becomes phosphorylated at Ser42in vivo, primarily in response to agents that cause DSBs (double-strand breaks). DSB-induced FUS phosphorylation in vivo at Ser42 requires ATM and not DNA-PK. Although Ser42 is retained in the oncogenic FUS–CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein 10] fusion generated by a t(12;16)(q13;p11) chromosomal translocation, Ser42 in FUS–CHOP is not phosphorylated after DNA damage. These results identify FUS as a new target of the ATM-signalling pathway and strengthen the notion that FUS regulates genome stability.

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Authors
Gardiner, M., Toth, R., Vandermoere, F., Morrice, N. A., & Rouse, J.
Affiliations
University of Dundee (GB)
Venue
Biochemical Journal
Published
2008-09-25
Volume
415
Issue
2
Pages
297-307
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
OpenAlex
W2023532020
Cited by
111
References
53
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 8 · 2022: 6 · 2021: 12 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 6 · 2016: 11 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 5
FWCI
2.47
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, other-oa)
Funders
Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
FUS, TLS, ATM, PIKK kinases, protein phosphorylation, DNA double-strand breaks, DNA damage response, genome stability, chromosomal instability, DNA-binding proteins
MeSH terms
Amino Acid Sequence, Cell Line, Chromatography, Affinity, DNA Damage, DNA-Binding Proteins, Humans, Molecular Sequence Data, Phosphorylation, Recombinant Fusion Proteins, Serine, Mass Spectrometry, Ultraviolet Rays, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Cell Cycle Proteins, Tumor Suppressor Proteins, RNA-Binding Protein FUS, DNA-Activated Protein Kinase, Ataxia Telangiectasia Mutated Proteins

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