NUT Is a Driver of p300-Mediated Histone Hyperacetylation: From Spermatogenesis to Cancer.
NUT Is a Driver of p300-Mediated Histone Hyperacetylation: From Spermatogenesis to Cancer.
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DOI：
10.3390/cancers14092234
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发表时间：
2022-04-29
期刊：
影响因子：
5.2
通讯作者：
Khochbin, Saadi
中科院分区：
文献类型：
--
作者：
Rousseaux, Sophie;Reynoird, Nicolas;Khochbin, Saadi
关键词：
BRD4-NUT融合蛋白作为高侵袭性NUT癌驱动因子的功能特征，对于理解组蛋白在精子细胞成熟的最后阶段被清除之前全基因组超乙酰化的机制至关重要。在成熟的精子细胞中，主要的基因组重组发生，其中包括在被精蛋白取代之前，组蛋白乙酰化的全球增加，后者负责男性基因组的紧密包装。了解致癌BRD4-NUT融合蛋白在NUT癌（NC）细胞中的功能，对于揭示生精细胞中组蛋白超乙酰化的机制至关重要。事实上，这些研究揭示了BRD4 （BET家族的溴结构域因子）、NUT（睾丸特异性因子）和组蛋白乙酰转移酶p300之间的合作机制，诱导了NC细胞中存在的高乙酰化染色质结构域的产生。nutko小鼠的产生使我们能够证明Nut和Brdt之间的遗传相互作用，编码Brdt，一种睾丸特异性brd4样因子。事实上，在生精细胞中，NUT和p300相互作用，导致组蛋白H4在K5和K8位点的乙酰化增加。当这两个位置都乙酰化时，BRDT的第一个溴域特异性识别，然后介导组蛋白的去除并由蛋白替代。综上所述，这些研究表明，在NUT癌细胞中，NUT与BRD4的融合在体细胞中重建了一个功能环，该功能环通常驱动生精细胞中组蛋白超乙酰化和染色质结合。
The functional characterization of the BRD4-NUT fusion protein as the driver of the highly aggressive NUT Carcinoma is fundamental to the understanding of the mechanisms responsible for the genome-wide hyperacetylation of histones prior to their eviction during the final stages of sperm cells maturation. In maturing sperm cells, a major genome re-organization takes place, which includes a global increase in the acetylation of histones prior to their replacement by protamines, the latter being responsible for the tight packaging of the male genome. Understanding the function of the oncogenic BRD4-NUT fusion protein in NUT carcinoma (NC) cells has proven to be essential in uncovering the mechanisms underlying histone hyperacetylation in spermatogenic cells. Indeed, these studies have revealed the mechanism by which a cooperation between BRD4, a bromodomain factor of the BET family, NUT, a normally testis-specific factor, and the histone acetyltransferase p300, induces the generation of hyperacetylated chromatin domains which are present in NC cells. The generation of Nut ko mice enabled us to demonstrate a genetic interaction between Nut and Brdt, encoding BRDT, a testis-specific BRD4-like factor. Indeed, in spermatogenic cells, NUT and p300 interact, which results in an increased acetylation of histone H4 at both positions K5 and K8. These two positions, when both acetylated, are specifically recognized by the first bromodomain of BRDT, which then mediates the removal of histone and their replacement by protamines. Taken together, these investigations show that the fusion of NUT to BRD4 in NUT Carcinoma cells reconstitutes, in somatic cells, a functional loop, which normally drives histone hyperacetylation and chromatin binding by a BET factor in spermatogenic cells.
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影响因子：
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