Nuclear receptor-induced transcription is driven by spatially and timely restricted waves of ROS. The role of Akt, IKKα, and DNA damage repair enzymes.
Nuclear receptor-induced transcription is driven by spatially and timely restricted waves of ROS. The role of Akt, IKKα, and DNA damage repair enzymes.
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DOI：
10.4161/nucl.36274
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Migliaccio A
中科院分区：
文献类型：
--
作者：
Perillo B;Di Santi A;Cernera G;Ombra MN;Castoria G;Migliaccio A
基因表达主要通过核小体组蛋白N-末端的翻译后修饰受染色质控制。根据组蛋白密码理论，一组特殊的此类修饰（标记）会对转录产生可重复的最终影响，最近，相邻残基特定标记之间的二元开关凸显了更高水平的复杂性。特别是，组蛋白H3中的二甲基赖氨酸9的消失面临着在基因表达激活过程中随后丝氨酸的磷酸化。赖氨酸特异性脱甲基酶1（LSD 1）对赖氨酸9的脱甲基化是将磷酰基标记添加到丝氨酸10的先决条件，并且是雌激素转录控制中的必要步骤。它产生氧反应性物质（ROS）的局部爆发，其诱导附近核苷酸的氧化和修复酶的募集，从而在DNA上形成单链或双链切口，其改变染色质柔性以允许转录机器的正确组装。 我们在这里描述的分子机制，通过它的核受体家族的成员防止潜在的损伤DNA在转录过程中引起的使用ROS染色质的形状的靶基因。其机制是基于组蛋白H3中磷酸化丝氨酸10的存在，以防止不平衡的DNA氧化波。我们还讨论了使用自愿紊乱的伺服系统，以诱导选择性死亡的转化细胞的机会。
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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