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Science 319 (5860): 202-206

Copyright © 2008 by the American Association for the Advancement of Science

DNA Oxidation as Triggered by H3K9me2 Demethylation Drives Estrogen-Induced Gene Expression

Bruno Perillo,1*{dagger} Maria Neve Ombra,1* Alessandra Bertoni,2 Concetta Cuozzo,3 Silvana Sacchetti,3 Annarita Sasso,2 Lorenzo Chiariotti,2 Antonio Malorni,1 Ciro Abbondanza,4 Enrico V. Avvedimento2{dagger}

Abstract: Modifications at the N-terminal tails of nucleosomal histones are required for efficient transcription in vivo. We analyzed how H3 histone methylation and demethylation control expression of estrogen-responsive genes and show that a DNA-bound estrogen receptor directs transcription by participating in bending chromatin to contact the RNA polymerase II recruited to the promoter. This process is driven by receptor-targeted demethylation of H3 lysine 9 at both enhancer and promoter sites and is achieved by activation of resident LSD1 demethylase. Localized demethylation produces hydrogen peroxide, which modifies the surrounding DNA and recruits 8-oxoguanine–DNA glycosylase 1 and topoisomeraseIIβ, triggering chromatin and DNA conformational changes that are essential for estrogen-induced transcription. Our data show a strategy that uses controlled DNA damage and repair to guide productive transcription.

1 Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche (C.N.R.), 83100 Avellino, Italy.
2 Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," Università degli Studi "Federico II," 80131 Naples, Italy.
3 Naples Oncogenomic Center, Centro di Ingegneria Genetica (CEINGE), Biotecnologie Avanzate, 80131 Naples, Italy.
4 Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, 80138 Naples, Italy.

* These authors contributed equally to this paper.

{dagger} To whom correspondence should be addressed. E-mail: perillo{at}unina.it (B.P.); avvedim{at}unina.it (E.V.A.)

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