CICICA, Centro de Investigación en Cirugía y Cáncer Research Center on Surgery and Cancer, Universidad de Costa Rica, San José, Costa Rica.
Programa de Doctorado en Ciencias, Sistema de Estudios de Posgrado (SEP), Universidad de Costa Rica, San José, Costa Rica.
Cancer Med. 2023 Dec;12(24):22130-22155. doi: 10.1002/cam4.6719. Epub 2023 Nov 21.
The gene dosage compensation hypothesis presents a mechanism through which the expression of certain genes is modulated to compensate for differences in the dose of genes when additional chromosomes are present. It is one of the means through which cancer cells actively cope with the potential damaging effects of aneuploidy, a hallmark of most cancers. Dosage compensation arises through several processes, including downregulation or overexpression of specific genes and the relocation of dosage-sensitive genes. In cancer, a majority of compensated genes are generally thought to be regulated at the translational or post-translational level, and include the basic components of a compensation loop, including sensors of gene dosage and modulators of gene expression. Post-translational regulation is mostly undertaken by a general degradation or aggregation of remaining protein subunits of macromolecular complexes. An increasingly important role has also been observed for transcriptional level regulation. This article reviews the process of targeted gene dosage compensation in cancer and other biological conditions, along with the mechanisms by which cells regulate specific genes to restore cellular homeostasis. These mechanisms represent potential targets for the inhibition of dosage compensation of specific genes in aneuploid cancers. This article critically examines the process of targeted gene dosage compensation in cancer and other biological contexts, alongside the criteria for identifying genes subject to dosage compensation and the intricate mechanisms by which cells orchestrate the regulation of specific genes to reinstate cellular homeostasis. Ultimately, our aim is to gain a comprehensive understanding of the intricate nature of a systems-level property. This property hinges upon the kinetic parameters of regulatory motifs, which we have termed "gene dosage sensor loops." These loops have the potential to operate at both the transcriptional and translational levels, thus emerging as promising candidates for the inhibition of dosage compensation in specific genes. Additionally, they represent novel and highly specific therapeutic targets in the context of aneuploid cancer.
基因剂量补偿假说提出了一种机制，通过该机制，某些基因的表达可以被调节，以补偿额外染色体存在时基因剂量的差异。这是癌细胞积极应对非整倍体潜在破坏性影响的手段之一，非整倍体是大多数癌症的标志。剂量补偿通过几种过程产生，包括特定基因的下调或过表达以及剂量敏感基因的重定位。在癌症中，大多数补偿基因通常被认为是在翻译或翻译后水平上受到调节的，并且包括补偿环的基本组成部分，包括基因剂量的传感器和基因表达的调节剂。翻译后调节主要通过大分子复合物的剩余蛋白质亚基的普遍降解或聚集来进行。转录水平调节也发挥了越来越重要的作用。本文综述了癌症和其他生物条件下靶向基因剂量补偿的过程，以及细胞调节特定基因以恢复细胞内稳态的机制。这些机制代表了抑制非整倍体癌症中特定基因剂量补偿的潜在靶点。本文批判性地检查了癌症和其他生物背景下靶向基因剂量补偿的过程，以及鉴定受剂量补偿影响的基因的标准，以及细胞协调特定基因调节以恢复细胞内稳态的复杂机制。最终，我们的目标是全面了解系统水平特性的复杂性质。该特性取决于调节基序的动力学参数，我们将其称为“基因剂量传感器环”。这些环有可能在转录和翻译水平上发挥作用，因此成为抑制特定基因剂量补偿的有前途的候选物。此外，它们在非整倍体癌症的背景下代表了新的和高度特异性的治疗靶点。
