DNA damage causes rapid accumulation of phosphoinositides for ATR signaling

Yu Hsiu Wang, Anushya Hariharan, Giulia Bastianello, Yusuke Toyama, G. V. Shivashankar, Marco Foiani, Michael Sheetz

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article number2118
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

ataxia
Ataxia Telangiectasia
Phosphatidylinositols
DNA Damage
lipids
deoxyribonucleic acid
inositols
damage
proteins
causes
Lipids
DNA
Proteins
lipid metabolism
activation
Chemical activation
asynchronous transfer mode
phosphorylation
Phosphorylation
Automatic teller machines

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Wang, Y. H., Hariharan, A., Bastianello, G., Toyama, Y., Shivashankar, G. V., Foiani, M., & Sheetz, M. (2017). DNA damage causes rapid accumulation of phosphoinositides for ATR signaling. Nature communications, 8(1), [2118]. https://doi.org/10.1038/s41467-017-01805-9

DNA damage causes rapid accumulation of phosphoinositides for ATR signaling. / Wang, Yu Hsiu; Hariharan, Anushya; Bastianello, Giulia; Toyama, Yusuke; Shivashankar, G. V.; Foiani, Marco; Sheetz, Michael.

In: Nature communications, Vol. 8, No. 1, 2118, 01.12.2017.

Research output: Contribution to journalArticle

Wang, YH, Hariharan, A, Bastianello, G, Toyama, Y, Shivashankar, GV, Foiani, M & Sheetz, M 2017, 'DNA damage causes rapid accumulation of phosphoinositides for ATR signaling', Nature communications, vol. 8, no. 1, 2118. https://doi.org/10.1038/s41467-017-01805-9
Wang YH, Hariharan A, Bastianello G, Toyama Y, Shivashankar GV, Foiani M et al. DNA damage causes rapid accumulation of phosphoinositides for ATR signaling. Nature communications. 2017 Dec 1;8(1). 2118. https://doi.org/10.1038/s41467-017-01805-9
Wang, Yu Hsiu ; Hariharan, Anushya ; Bastianello, Giulia ; Toyama, Yusuke ; Shivashankar, G. V. ; Foiani, Marco ; Sheetz, Michael. / DNA damage causes rapid accumulation of phosphoinositides for ATR signaling. In: Nature communications. 2017 ; Vol. 8, No. 1.
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