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Sci. Signal., 24 November 2009
Vol. 2, Issue 98, p. ec378
[DOI: 10.1126/scisignal.298ec378]

EDITORS' CHOICE

Cell Biology PARt of the Response to DNA Damage

Wei Wong

Science Signaling, AAAS, Washington, DC 20005, USA

Double-stranded DNA breaks, such as those caused by radiation, activate DNA damage responses. One such response is gene transcription by nuclear factor {kappa}B (NF-{kappa}B); activation of this transcription factor requires several upstream signaling events, including sumoylation of I{kappa}B kinase {gamma} [IKK{gamma}; also known as NF-{kappa}B essential modulator (NEMO)] by protein inhibitor of activated STAT y (PIASy) and phosphorylation of IKK{gamma} by the kinase ataxia telangiectasia mutated (ATM) (see also McCool and Miyamoto). To investigate how PIASy and ATM are recruited to IKK{gamma}, Stilmann et al. searched for binding partners of IKK{gamma} and identified poly(ADP-ribose)-polymerase 1 (PARP-1). In contrast to cells from wild-type mice, cells from Parp1–/– mice did not show NF-{kappa}B activation in response to radiation, as assessed by nuclear accumulation of the p65 subunit of NF-{kappa}B in mouse embryonic fibroblasts (MEFs) and electrophoretic mobility shift assays (EMSAs) in macrophages and small intestinal epithelial cells. NF-{kappa}B activation in Parp1–/– MEFs was rescued by expressing wild-type PARP-1, but not a catalytically inactive mutant or a mutant unable to bind DNA. The association of endogenous PARP-1 with IKK{gamma} was induced by irradiation, transient in nature, and required poly(ADP-ribosyl)ation. Furthermore, PARP-1 enhanced the interaction between IKK{gamma} and PIASy [an effect that required poly(ADP-ribose) binding motifs in PIASy], was required for sumoylation of IKK{gamma} by PIASy, and promoted the association of ATM with IKK{gamma} and PIASy. Parp1–/– MEFs were more sensitive to irradiation-induced apoptosis compared with wild-type MEFs; in addition, induction of NF-{kappa}B target genes that counter apoptosis was impaired in Parp1–/– MEFs. The authors propose that DNA damage stimulates PARP-1, which, through poly(ADP-ribosyl)ation, mediates the formation of a complex that enables the phosphorylation of IKK{gamma} by ATM, the sumoylation of IKK{gamma} by PIASy, and ultimately the activation of NF-{kappa}B.

M. Stilmann, M. Hinz, S. Ç. Arslan, A. Zimmer, V. Schreiber, C. Scheidereit, A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced I{kappa}B kinase activation. Mol. Cell 36, 365–378 (2009). [PubMed]

K. McCool, S. Miyamoto, A PAR-SUMOnious mechanism of NEMO activation. Mol. Cell 36, 349–350 (2009). [PubMed]

Citation: W. Wong, PARt of the Response to DNA Damage. Sci. Signal. 2, ec378 (2009).

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