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Nuclear matrix: application to diagnosis of cancer and role in transcription and modulation of chromatin structure

机译：核基质：在癌症诊断中的应用以及在染色质结构的转录和调节中的作用

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The nuclear matrix is involved in the processing of the genetic information and in the organization of chromatin. In recent years we have come to appreciate the organization of functional domains within the nucleus (e.g., transcript domains, RNA processing sites, sites of replication). The nuclear matrix is the foundation from which this organization is built, providing a scaffold upon which nuclear processes such as DNA replication and transcription occur. Chromatin is arranged into loop domains through the attachment of matrix associated regions (MARs) at the base of the loop to nuclear matrix proteins. Considering the role of the nuclear matrix in the organization and processing of the genetic information, it is not surprising to find that nuclear matrix proteins are informative in distinguishing cell types and disease states. For example, nuclear matrix proteins informative in the diagnosis of cancer, including breast cancer have been identified. Typically nuclear matrices are obtained following the salt extraction of nuclease-digested nuclei. However, recent studies show that cisplatin preferentially crosslinks MAR DNA to nuclear matrix proteins in situ, providing a complimentary method to identify informative nuclear matrix proteins.Transcribed, but not repressed chromatin, is associated with the nuclear matrix. Regions of a chromatin loop engaged in transcription are associated with the nuclear matrix through multiple dynamic interactions with nuclear matrix proteins. Nuclear matrix bound transcription factors, the transcription machinery and histone modifying enzymes are thought to mediate these dynamic attachments between the nuclear matrix and transcriptionally active chromatin. Core histones of transcriptionally active chromatin are dynamically acetylated, with histone acetyltransferases (HATs) and deacetylases (HDACs) catalyzing this reaction. Both of these enzymes, which are now known to be transcriptional coactivators and modulators, are associated with the nuclear matrix. We have proposed that these enzymes participate in the dynamic attachment of transcriptionally active chromatin with the nuclear matrix. Our recent studies show that cisplatin crosslinks nuclear matrix-bound transcription factors and transcription modulators to nuclear DNA in situ. This suggests that cisplatin will be most useful in the discovery of nuclear matrix MAR binding proteins involved in the organization of DNA and nuclear matrix bound transcription factors/modulators participating in the nuclear matrix association of transcriptionally active chromatin. (Supported by Medical Research Council of Canada)
机译：核基质参与遗传信息的处理和染色质的组织。近年来，我们已经开始欣赏细胞核内功能域的组织（例如，转录域，RNA加工位点，复制位点）。核基质是建立该组织的基础，提供了一个支架，在支架上会发生诸如DNA复制和转录的核过程。染色质通过环底部的基质相关区域（MARs）与核基质蛋白的连接而排列成环结构域。考虑到核基质在遗传信息的组织和处理中的作用，发现核基质蛋白在区分细胞类型和疾病状态方面提供信息不足为奇。例如，已经鉴定出对包括乳腺癌在内的癌症的诊断有用的核基质蛋白。通常，在用核酸酶消化的细胞核盐提取后获得细胞核基质。然而，最近的研究表明，顺铂优先将MAR DNA交联到原位的核基质蛋白上，为鉴定信息丰富的核基质蛋白提供了一种补充方法。转录但未抑制的染色质与核基质有关。参与转录的染色质环区域通过与核基质蛋白的多种动态相互作用而与核基质相关联。核基质结合的转录因子，转录机制和组蛋白修饰酶被认为介导了核基质与转录活性染色质之间的这些动态连接。转录活性染色质的核心组蛋白被动态乙酰化，组蛋白乙酰转移酶（HATs）和脱乙酰基酶（HDACs）催化该反应。现在已知这两种酶是转录共激活剂和调节剂，都与核基质有关。我们已经提出，这些酶参与转录活性染色质与核基质的动态结合。我们最近的研究表明，顺铂将核基质结合的转录因子和转录调节剂原位交联到核DNA。这表明顺铂将在发现参与DNA组织的核基质MAR结合蛋白和参与转录活性染色质核基质结合的核基质结合转录因子/调节剂的发现中最有用。 （由加拿大医学研究理事会支持）

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