Editors' ChoiceCell Biology

IP6K1 Sees the Light

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Sci. Signal.  18 Nov 2014:
Vol. 7, Issue 352, pp. ec321
DOI: 10.1126/scisignal.aaa2973

Exposure to ultraviolet (UV) induces DNA damage, cell cycle arrest, and apoptosis. The multiprotein complex Cullin–RING ubiquitin ligase 4 (CRL4) responds to DNA damage by ubiquitylating several proteins involved in regulating the cell cycle, cell growth, and nucleotide excision repair (NER). Binding and deneddylation by the COP9 signalosome complex inhibits CRL4 activity, and UV irradiation dissociates the interaction between CRL4 and COP9. Inositol pyrophosphates (IP) with seven phosphates (IP7) are primarily formed by phosphorylation of IP6 by IP6 kinases (IP6Ks) and are involved in diverse cellular processes. Rao et al. found that IP6K1 bound to DDB1, an adaptor component of CRL4. Overexpression of IP6K1 inhibited the activity of overexpressed CRL4 in human embryonic kidney 293 (HEK293) cells. The basal abundances of the CRL4 substrates p27 (an inhibitor of the cell cycle) and c-Jun (a transcription factor involved in stress responses) were reduced in mouse embryonic fibroblasts (MEFs) deficient for IP6K1, and the basal abundances of the CRL4 substrates p21 (an inhibitor of the cell cycle) and p53 (a transcription factor involved in stress responses) were reduced in HCT116 colon cancer cells in which IP6K1 was knocked down. UV-induced degradation of the CRL4 substrate CDT1 (a DNA replication factor) and NER of cyclobutane pyrimidine dimers were enhanced in IP6K1-deficient MEFs, and IP6K1-MEFs were resistant to UV-induced apoptosis. IP6K1 formed a ternary complex with CRL4 and COP9. Overexpression of IP6K1 enhanced the interaction of CRL4 and COP9, whereas IP6K1 knockdown decreased the interaction of CRL4 and COP9 and enhanced neddylation of CRL4. UV irradiation reduced the interaction between CRL4 and COP9 in wild-type, but not IP6K1-deficient, MEFs. UV irradiation inhibited the interaction between CRL4 and wild-type IP6K1, but not kinase-dead IP6K1. Pharmacological inhibition of IP6K1 increased the interaction between CRL4 and COP9, decreased neddylation of CRL4, and inhibited the UV-induced dissociation of CRL4 and COP9. UV irradiation increased the production of IP7 in HEK293 cells and DDB1 inhibited the ability of IP6K1 to phosphorylated IP6 in vitro. Thus, UV exposure dissociates the IP6K1-CRL4-COP9 ternary complex, promoting the activities of CRL4 and IP6K1 to respond to cellular stress.

F. Rao, J. Xu, A. B. Khan, M. M. Gadalla, J. Y. Cha, R. Xu, R. Tyagi, Y. Dang, A. Chakraborty, S. H. Snyder, Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4–signalosome complex to regulate DNA repair and cell death. Proc. Natl. Acad. Sci. U.S.A. 111, 16005–16010 (2014). [Abstract] [Full Text]