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https://doi.org/10.1038/s41467-017-01805-9
Title: | DNA damage causes rapid accumulation of phosphoinositides for ATR signaling | Authors: | Wang, Y.-H Hariharan, A Bastianello, G Toyama, Y Shivashankar, G.V Foiani, M Sheetz, M.P |
Keywords: | actin ATR protein cell nucleus receptor checkpoint kinase 1 inositol polyphosphate inositol polyphosphate multikinase latrunculin A messenger RNA nuclear protein nuclear receptor protein SF1 phosphatidylinositide unclassified drug wortmannin ATM protein ATR protein, human checkpoint kinase 1 CHEK1 protein, human inositol polyphosphate multikinase phosphatidylinositol phosphotransferase steroidogenic factor 1 chemical reaction DNA enzyme enzyme activity metabolism nervous system disorder protein animal cell Article controlled study DNA damage response DNA repair embryo enzyme activation enzyme phosphorylation gene expression lipid storage mouse nonhuman phosphoinositide metabolism pleckstrin homology domain protein assembly protein binding protein depletion protein expression RNA splicing signal transduction animal cell line DNA damage genetics human metabolism RNA interference signal transduction tumor cell line Animals Ataxia Telangiectasia Mutated Proteins Cell Line Cell Line, Tumor Checkpoint Kinase 1 DNA Damage DNA Repair Humans Mice Phosphatidylinositols Phosphotransferases (Alcohol Group Acceptor) RNA Interference Signal Transduction Steroidogenic Factor 1 |
Issue Date: | 2017 | Publisher: | Nature Publishing Group | Citation: | Wang, Y.-H, Hariharan, A, Bastianello, G, Toyama, Y, Shivashankar, G.V, Foiani, M, Sheetz, M.P (2017). DNA damage causes rapid accumulation of phosphoinositides for ATR signaling. Nature Communications 8 (1) : 2118. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-017-01805-9 | Abstract: | Phosphoinositide lipids (PPIs) are enriched in the nucleus and are accumulated at DNA damage sites. Here, we investigate roles of nuclear PPIs in DNA damage response by sequestering specific PPIs with the expression of nuclear-Targeted PH domains, which inhibits recruitment of Ataxia telangiectasia and Rad3-related protein (ATR) and reduces activation of Chk1. PPI-binding domains rapidly (< 1 s) accumulate at damage sites with local enrichment of PPIs. Accumulation of PIP3 in complex with the nuclear receptor protein, SF1, at damage sites requires phosphorylation by inositol polyphosphate multikinase (IPMK) and promotes nuclear actin assembly that is required for ATR recruitment. Suppressed ATR recruitment/activation is confirmed with latrunculin A and wortmannin treatment as well as IPMK or SF1 depletion. Other DNA repair pathways involving ATM and DNA-PKcs are unaffected by PPI sequestration. Together, these findings reveal that nuclear PPI metabolism mediates an early damage response through the IPMK-dependent pathway to specifically recruit ATR. © 2017 The Author(s). | Source Title: | Nature Communications | URI: | https://scholarbank.nus.edu.sg/handle/10635/174372 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-017-01805-9 |
Appears in Collections: | Elements Staff Publications |
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