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 PIP3in 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.

DNA damage causes rapid accumulation of phosphoinositides for ATR signaling / Y. Wang, A. Hariharan, G. Bastianello, Y. Toyama, G.V. Shivashankar, M. Foiani, M.P. Sheetz. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 8:1(2017 Dec 14). [10.1038/s41467-017-01805-9]

DNA damage causes rapid accumulation of phosphoinositides for ATR signaling

G. Bastianello;M. Foiani
Penultimo
;
2017

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 PIP3in 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.
English
chemistry (all); biochemistry, genetics and molecular biology (all); physics and astronomy (all)
Settore BIO/11 - Biologia Molecolare
Articolo
Esperti anonimi
Ricerca di base
Pubblicazione scientifica
14-dic-2017
Nature Publishing Group
8
1
2118
15
Pubblicato
Periodico con rilevanza internazionale
scopus
pubmed
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info:eu-repo/semantics/article
DNA damage causes rapid accumulation of phosphoinositides for ATR signaling / Y. Wang, A. Hariharan, G. Bastianello, Y. Toyama, G.V. Shivashankar, M. Foiani, M.P. Sheetz. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 8:1(2017 Dec 14). [10.1038/s41467-017-01805-9]
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Y. Wang, A. Hariharan, G. Bastianello, Y. Toyama, G.V. Shivashankar, M. Foiani, M.P. Sheetz
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/562098
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