Open AccessArtemis‐dependent DNA double‐strand break formation at stalled replication forks
Author(s) -
Unno Junya,
Takagi Masatoshi,
Piao Jinhua,
Sugimoto Masataka,
Honda Fumiko,
Maeda Daisuke,
Masutani Mitsuko,
Kiyono Tohru,
Watanabe Fumiaki,
Morio Tomohiro,
Teraoka Hirobumi,
Mizutani Shuki
Publication year - 2013
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12144
Subject(s) - microbiology and biotechnology , dna replication , dna pkcs , biology , eukaryotic dna replication , protein subunit , replication factor c , dna , origin recognition complex , kinase , chemistry , genetics , protein kinase a , gene
Stalled replication forks undergo DNA double‐strand breaks ( DSB s) 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, DSB s are generated in an A rtemis 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 A rtemis, is also required for DSB generation and subsequent ATM activation. Our findings indicate a novel function of A rtemis as a molecular switch that converts stalled replication forks harboring single‐stranded gap DNA lesions into DSB s, thereby activating the ATM signaling pathway following prolonged replication fork stalling.