DNA Damage Causes Rapid Accumulation of Phosphoinositides for ATR signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Dec 16

PMID 29242514

Citations 43

Authors

Yu-Hsiu Wang

Anushya Hariharan

Giulia Bastianello

Yusuke Toyama

G V Shivashankar

Marco Foiani

Michael P Sheetz

Affiliations

Soon will be listed here.

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 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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