title: Artemis-dependent DNA double-strand break formation at stalled replication forks.
abstract: Stalled replication forks undergo DNA double-strand breaks (DSBs) under certain conditions. However, the precise mechanism underlying DSB induction and the cellular response to persistent replication fork stalling are not fully understood. Here we show that, in response to hydroxyurea exposure, DSBs are generated in an Artemis nuclease-dependent manner following prolonged stalling with subsequent activation of the ataxia-telangiectasia mutated (ATM) signaling pathway. The kinase activity of the catalytic subunit of the DNA-dependent protein kinase, a prerequisite for stimulation of the endonuclease activity of Artemis, is also required for DSB generation and subsequent ATM activation. Our findings indicate a novel function of Artemis as a molecular switch that converts stalled replication forks harboring single-stranded gap DNA lesions into DSBs, thereby activating the ATM signaling pathway following prolonged replication fork stalling.
authors: Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Junya
authors: J
authors: Unno
authors: Masatoshi
authors: M
authors: Takagi
authors: Jinhua
authors: J
authors: Piao
authors: Masataka
authors: M
authors: Sugimoto
authors: Fumiko
authors: F
authors: Honda
authors: Daisuke
authors: D
authors: Maeda
authors: Mitsuko
authors: M
authors: Masutani
authors: Tohru
authors: T
authors: Kiyono
authors: Fumiaki
authors: F
authors: Watanabe
authors: Tomohiro
authors: T
authors: Morio
authors: Hirobumi
authors: H
authors: Teraoka
authors: Shuki
authors: S
authors: Mizutani
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004720:Endonucleases; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C426344:DCLRE1C protein, human; D004720:Endonucleases