Gene expression is governed by chromatin mainly through posttranslational modifications at the N-terminal tails of nucleosomal histone proteins. According to the histone code theory, peculiar sets of such modifications (marks) give rise to reproducible final effects on transcription and, very recently, a further level of complexity has been highlighted in binary switches between specific marks at adjacent residues. In particular, disappearance of dimethyl-lysine 9 in histone H3 is faced by phosphorylation of the following serine during activation of gene expression. Demethylation of lysine 9 by the lysine-specific demethylase 1 (LSD1) is a pre-requisite for addition of the phosphoryl mark to serine 10 and an essential step in the transcriptional control by estrogens. It generates a local burst of oxygen reactive species (ROS) that induce oxidation of nearby nucleotides and recruitment of repair enzymes with a consequent formation of single or double stranded nicks on DNA that modify chromatin flexibility in order to allow correct assembly of the transcriptional machinery. We describe here the molecular mechanism by which members of the family of nuclear receptors prevent the potential damage to DNA during transcription of target genes elicited by the use of ROS to shape chromatin. The mechanism is based on the presence of phosphorylated serine 10 in histone H3 to prevent unbalanced DNA oxidation waves. We also discuss the opportunities raised by the use of voluntary derangement of this servo system to induce selective death in hormone-responsive transformed cells.

Nuclear receptor-induced transcription is driven by spatially and timely restricted waves of ROS. The role of Akt, IKKα, and DNA damage repair enzymes

Di Santi, Annalisa;Cernera, Gustavo;
2014

Abstract

Gene expression is governed by chromatin mainly through posttranslational modifications at the N-terminal tails of nucleosomal histone proteins. According to the histone code theory, peculiar sets of such modifications (marks) give rise to reproducible final effects on transcription and, very recently, a further level of complexity has been highlighted in binary switches between specific marks at adjacent residues. In particular, disappearance of dimethyl-lysine 9 in histone H3 is faced by phosphorylation of the following serine during activation of gene expression. Demethylation of lysine 9 by the lysine-specific demethylase 1 (LSD1) is a pre-requisite for addition of the phosphoryl mark to serine 10 and an essential step in the transcriptional control by estrogens. It generates a local burst of oxygen reactive species (ROS) that induce oxidation of nearby nucleotides and recruitment of repair enzymes with a consequent formation of single or double stranded nicks on DNA that modify chromatin flexibility in order to allow correct assembly of the transcriptional machinery. We describe here the molecular mechanism by which members of the family of nuclear receptors prevent the potential damage to DNA during transcription of target genes elicited by the use of ROS to shape chromatin. The mechanism is based on the presence of phosphorylated serine 10 in histone H3 to prevent unbalanced DNA oxidation waves. We also discuss the opportunities raised by the use of voluntary derangement of this servo system to induce selective death in hormone-responsive transformed cells.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/893181
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