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Review
. 2023 Dec;12(24):22130-22155.
doi: 10.1002/cam4.6719. Epub 2023 Nov 21.

Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems-level property in cancer

Diana M Bravo-Estupiñan  1   2   3   4 , Karol Aguilar-Guerrero  1   5 , Steve Quirós  1   6 , Man-Sai Acón  1 , Christian Marín-Müller  4 , Miguel Ibáñez-Hernández  3 , Rodrigo A Mora-Rodríguez  1   6
Affiliations
Review

Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems-level property in cancer

Diana M Bravo-Estupiñan et al. Cancer Med. 2023 Dec.

Abstract

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.

Keywords: aneuploidy; cancer; gene dosage compensation; miRNAs; systems biology.

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Conflict of interest statement

The authors have no relevant financial or non‐financial interests to disclose.

Figures

FIGURE 1
FIGURE 1
Gene dosage compensation. It represents a compensatory mechanism that might ameliorate the imbalanced expression of certain genes and restore protein homeostasis in aneuploid cells. These cells have compensatory mechanisms to obtain a similar protein expression (and function) compared to diploid conditions despite having an altered number of copies of a genes; compared to a non‐compensated gene where the number of protein or messenger RNA molecules (and thereby its function) significantly increases with an increased gene copy number (figure generated using Biorender.com).
FIGURE 2
FIGURE 2
Protein level compensation mechanisms. Several mechanisms have been described that exist for compensation of gene dose at the protein level. (A) miRNAs could regulate gene expression both at the post‐transcriptional level and at the translational level, depending on their complementarity and binding to different argonaute (Ago) proteins. (B) Ribosomes load at the 5′ end of the mRNA, when there is a uORF and in conditions of stress, some genes are downregulated by the ribosome loading in the uORF and either uncoupling, reinitiation the reading of the main open reading frame (mORF) or just elongating the uORF sequence. (C) In aneuploid conditions where protein subunits are encoded in aneuploid chromosomes, there is an overproduction of protein subunits, so this imbalance must be corrected by degradation by the ubiquitin–proteasome system or by aggregation (figure generated using Biorender.com).
FIGURE 3
FIGURE 3
Mechanisms of gene dosage compensation at the transcriptional level. Regulation of gene expression by compensation through different mechanisms. (A) LncRNAs can modify gene expression by directing specific transcription factors or chromatin remodelers to the regulatory regions of compensated genes by homologous base pairing or by specifically regulating the binding of chromatin‐modifying or non‐modifying proteins. (B) RNA‐binding protein (RBP) can also regulate gene expression in several ways, one of which is to increase gene expression by stabilizing mRNA. (C) The miRNAs can regulate the expression of genes that have altered the number of copies, joining mRNAs by complementary homologous bases in the 3′UTR region or using complex networks that involve sensor loops between transcription factors (TF) and miRNA (figure generated using Biorender.com).
FIGURE 4
FIGURE 4
Diagram of motifs enables adaptive gene expression in mammalian cells. (A) Positive feedback loop mediated by miRNA. In positive feedback loops, transient external cues can lead to a permanent transition from a miRNA‐induced TF suppression scenario to a permanent and expressive TF‐mediated miRNA suppression scenario. (B) Negative feedback loop mediated by miRNA. During negative feedback loops, the system maintains homeostasis and increases external signals, and the enhancement of expression of TFs compensates by increased expression of miRNAs so that TF levels remain stable over a wide range of external signal values. (C) miRNA‐mediated coherent feedforward loop. _target expression by TFs is regulated in two ways: directly, by inhibiting transcription of the _target gene, and indirectly, by enhancing the expression of miRNA that represses the _target gene. (D) miRNA‐mediated incoherent feedforward loop. _target expression by TFs is regulated in two ways: positively, by direct activation of the expression of _target genes, and negatively, by enhancing the expression of miRNAs that repress _target genes (figure generated using Biorender.com).
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