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

• DOI: 10.1042/bj20081135
• Publication Date: 2008-07-14T09:35:45Z
• Authors: Mary Gardiner; Rachel Toth; Franck Vandermoere; Nicholas A. Morrice; John Rouse
• Keywords: 570; 0303 health sciences; Sequence Homology, Amino Acid; Ultraviolet Rays; Recombinant Fusion Proteins; Tumor Suppressor Proteins; Molecular Sequence Data; 610; Cell Cycle Proteins; Ataxia Telangiectasia Mutated Proteins; DNA-Activated Protein Kinase; Protein Serine-Threonine Kinases; Chromatography, Affinity; Mass Spectrometry; Cell Line; DNA-Binding Proteins; 03 medical and health sciences; Serine; Humans; RNA-Binding Protein FUS; Amino Acid Sequence; Phosphorylation; DNA Damage

ATM (ataxia-telangiectasia mutated), ATR (ATM- and Rad3-related) DNA-PK (DNA-dependent protein kinase), important regulators of genome stability, belong to the PIKK (phosphoinositide 3-kinase-like kinase) family kinases. In present study, DNA-affinity chromatography was used identify DNA-binding proteins phosphorylated by these This resulted in identification FUS (fused sarcoma)/TLS (translocated liposarcoma) as an vitro target PIKKs. is a member Ewing's sarcoma that appears play role regulating since mice lacking show chromosomal instability defects meiosis. The residues are vivo were identified, phospho-specific antibodies generated demonstrate becomes at Ser(42) vivo, primarily response agents cause DSBs (double-strand breaks). DSB-induced phosphorylation requires not DNA-PK. Although retained oncogenic FUS-CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous 10] fusion t(12;16)(q13;p11) translocation, after DNA damage. These results new ATM-signalling pathway strengthen notion regulates stability.