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Cited by 94DNA Repair MechanismsProtein Kinase Regulation and GTPase SignalingEffects of Radiation Exposure

DNA Damage Causes Rapid Accumulation of Phosphoinositides for ATR Signaling

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Wang, Yu-Hsiu, Hariharan, Anushya, Bastianello, Giulia, Toyama, Yusuke, Shivashankar, G. V., Foiani, Marco, Sheetz, Michael P.·2017·Nature Communications
DOI 10.1038/s41467-017-01805-9PMC PMC5730617
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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 PIP 3 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.

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  • IPMK-generated PIP3 facilitates polymerization of nuclear actin, essential for recruitment of ATR and participating in replication stress and DNA repair.

    “Two notable studies by Wang et al. [59] and Lamm et al. [60] elucidated that IPMK-generated PIP3 facilitates the polymerization of nuclear actin, essential for the recruitment of ATR (ataxia telangiectasia and Rad3-related protein) and participating in replication stress and DNA repair processes.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [59]

    The Results report that IPMK activity is needed for PIP3 accumulation and that ATR recruitment depends on actin polymerization; the Discussion links nuclear phosphoinositides and actin to ATR recruitment at DNA-damage sites. The paper mentions ATR’s response to stalled replication forks, but the passages do not establish that the IPMK–PIP3–actin pathway participates in replication stress. It also presents PIP3-mediated actin polymerization as likely, rather than directly established. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Nuclear-derived PIP3 is implicated in DNA repair.

    “This nuclear-derived PIP3 is implicated in critical cellular processes such as DNA repair.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [59]

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Authors
Wang, Y.-H., Hariharan, A., Bastianello, G., Toyama, Y., Shivashankar, G. V., Foiani, M., & Sheetz, M. P.
Affiliations
  • National University of Singapore (SG)
  • University of Milan (IT)
  • Temasek Life Sciences Laboratory (SG)
Corresponding author
Sheetz, Michael P.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-12-14
Volume
8
Issue
1
Pages
2118-2118
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-01805-9
PMC
PMC5730617
OpenAlex
W2774985751
Cited by
94
References
1
Citations by year
2026: 13 · 2025: 12 · 2024: 12 · 2023: 12 · 2022: 7 · 2021: 7 · 2020: 13 · 2019: 13 · 2018: 5
FWCI
3.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Research Foundation
  • National University of Singapore
  • Mechanobiology Institute, Singapore
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Keywords
DNA damage response, phosphoinositides, ATR signaling, Chk1 activation, inositol polyphosphate multikinase, phosphatidylinositol 3,4,5-trisphosphate, ATM, DNA-PKcs, DNA repair
MeSH terms
Checkpoint Kinase 1, Animals, Cell Line, DNA Damage, DNA Repair, Humans, Phosphatidylinositols, Signal Transduction, Phosphotransferases (Alcohol Group Acceptor), RNA Interference, Cell Line, Tumor, Mice, Steroidogenic Factor 1, Ataxia Telangiectasia Mutated Proteins

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