Proteome dynamics at broken replication forks reveal a distinct ATM-directed repair response suppressing DNA double-strand break ubiquitination
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Proteome dynamics at broken replication forks reveal a distinct ATM-directed repair response suppressing DNA double-strand break ubiquitination. / Nakamura, Kyosuke; Kustatscher, Georg; Alabert, Constance; Hödl, Martina; Forne, Ignasi; Völker-Albert, Moritz; Satpathy, Shankha; Beyer, Tracey E; Mailand, Niels; Choudhary, Chunaram; Imhof, Axel; Rappsilber, Juri; Groth, Anja.
In: Molecular Cell, Vol. 81, No. 3, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Proteome dynamics at broken replication forks reveal a distinct ATM-directed repair response suppressing DNA double-strand break ubiquitination
AU - Nakamura, Kyosuke
AU - Kustatscher, Georg
AU - Alabert, Constance
AU - Hödl, Martina
AU - Forne, Ignasi
AU - Völker-Albert, Moritz
AU - Satpathy, Shankha
AU - Beyer, Tracey E
AU - Mailand, Niels
AU - Choudhary, Chunaram
AU - Imhof, Axel
AU - Rappsilber, Juri
AU - Groth, Anja
PY - 2021
Y1 - 2021
N2 - Cells have evolved an elaborate DNA repair network to ensure complete and accurate DNA replication. Defects in these repair machineries can fuel genome instability and drive carcinogenesis while creating vulnerabilities that may be exploited in therapy. Here, we use nascent chromatin capture (NCC) proteomics to characterize the repair of replication-associated DNA double-strand breaks (DSBs) triggered by topoisomerase 1 (TOP1) inhibitors. We reveal profound changes in the fork proteome, including the chromatin environment and nuclear membrane interactions, and identify three classes of repair factors according to their enrichment at broken and/or stalled forks. ATM inhibition dramatically rewired the broken fork proteome, revealing that ataxia telangiectasia mutated (ATM) signalling stimulates DNA end resection, recruits PLK1, and concomitantly suppresses the canonical DSB ubiquitination response by preventing accumulation of RNF168 and BRCA1-A. This work and collection of replication fork proteomes provide a new framework to understand how cells orchestrate homologous recombination repair of replication-associated DSBs.
AB - Cells have evolved an elaborate DNA repair network to ensure complete and accurate DNA replication. Defects in these repair machineries can fuel genome instability and drive carcinogenesis while creating vulnerabilities that may be exploited in therapy. Here, we use nascent chromatin capture (NCC) proteomics to characterize the repair of replication-associated DNA double-strand breaks (DSBs) triggered by topoisomerase 1 (TOP1) inhibitors. We reveal profound changes in the fork proteome, including the chromatin environment and nuclear membrane interactions, and identify three classes of repair factors according to their enrichment at broken and/or stalled forks. ATM inhibition dramatically rewired the broken fork proteome, revealing that ataxia telangiectasia mutated (ATM) signalling stimulates DNA end resection, recruits PLK1, and concomitantly suppresses the canonical DSB ubiquitination response by preventing accumulation of RNF168 and BRCA1-A. This work and collection of replication fork proteomes provide a new framework to understand how cells orchestrate homologous recombination repair of replication-associated DSBs.
U2 - 10.1016/j.molcel.2020.12.025
DO - 10.1016/j.molcel.2020.12.025
M3 - Journal article
C2 - 33450211
VL - 81
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 3
ER -
ID: 255561231