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Nat Commun. 2017 Dec 14;8(1):2118. doi: 10.1038/s41467-017-01805-9.

DNA damage causes rapid accumulation of phosphoinositides for ATR signaling.

Author information

1
Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.
2
IFOM, the FIRC Institute of Molecular Oncology, Via Adamello, 16-20139, Milan, Italy.
3
Università degli Studi di Milano, 20133, Milan, Italy.
4
Temasek Life Sciences Laboratory, 1 Research Link, Singapore, 117604, Singapore.
5
Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore.
6
Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore. ms2001@columbia.edu.
7
Department of Biological Sciences, Columbia University, New York, NY, 10027, USA. ms2001@columbia.edu.

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.

PMID:
29242514
PMCID:
PMC5730617
DOI:
10.1038/s41467-017-01805-9
[Indexed for MEDLINE]
Free PMC Article

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