Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the crl4-signalosome complex to regulate DNA repair and cell death

Feng Rao, Jing Xu, A. Basit Khan, Moataz M. Gadalla, Jiyoung Y. Cha, Risheng Xu, Richa Tyagi, Yongjun Dang, Anutosh Chakraborty, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

Abstract

Inositol polyphosphates containing an energetic pyrophosphate bond are formed primarily by a family of three inositol hexakisphosphate (IP6) kinases (IP6K1-3). The Cullin-RING ubiquitin ligases (CRLs) regulate diverse biological processes through substrate ubiquitylation. CRL4, comprising the scaffold Cullin 4A/B, the E2-interacting Roc1/2, and the adaptor protein damage-specific DNA-binding protein 1, is activated by DNA damage. Basal CRL4 activity is inhibited by binding to the COP9 signalosome (CSN). UV radiation and other stressors dissociate the complex, leading to E3 ligase activation, but signaling events that trigger signalosome dissociation from CRL4 have been unclear. In the present study, we show that, under basal conditions, IP6K1 formsa ternary complex with CSN and CRL4 in which IP6K1 and CRL4 are inactive. UV dissociates IP6K1 to generate IP7, which then dissociates CSN-CRL4 to activate CRL4. Thus, IP6K1 is a novel CRL4 subunit that transduces UV signals to mediate disassembly of the CRL4-CSN complex, thereby regulating nucleotide excision repair and cell death.

Original languageEnglish (US)
Pages (from-to)16005-16010
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number45
DOIs
StatePublished - Nov 11 2014

Keywords

  • Cullin ring E3 ligases
  • DNA repair
  • Inositol phosphates
  • Signalosome
  • UV radiation

ASJC Scopus subject areas

  • General

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