Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies

Mészáros, Bálint; Hajdu-Soltész, Borbála; Zeke, András; Dosztányi, Zsuzsanna

doi:10.3390/biom11030381

Cited by 32 publications

(26 citation statements)

References 118 publications

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“…Disordered regions reportedly are frequent targets for positive selection [ 33 , 67 ] but are also shown to be associated with many human diseases when mutated [ 68 – 70 ]. Our results from the analysis of variants from relatively healthy individuals in the general population [ 40 ], support the concept underlying the former observation, that is owing to the lack of structural constraints, IDRs evolve relatively fast yet are usually able to preserve their function [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of intrinsically disordered regions in proteins informed by human genetic diversity

et al. 2022

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All proteomes contain both proteins and polypeptide segments that don’t form a defined three-dimensional structure yet are biologically active—called intrinsically disordered proteins and regions (IDPs and IDRs). Most of these IDPs/IDRs lack useful functional annotation limiting our understanding of their importance for organism fitness. Here we characterized IDRs using protein sequence annotations of functional sites and regions available in the UniProt knowledgebase (“UniProt features”: active site, ligand-binding pocket, regions mediating protein-protein interactions, etc.). By measuring the statistical enrichment of twenty-five UniProt features in 981 IDRs of 561 human proteins, we identified eight features that are commonly located in IDRs. We then collected the genetic variant data from the general population and patient-based databases and evaluated the prevalence of population and pathogenic variations in IDPs/IDRs. We observed that some IDRs tolerate 2 to 12-times more single amino acid-substituting missense mutations than synonymous changes in the general population. However, we also found that 37% of all germline pathogenic mutations are located in disordered regions of 96 proteins. Based on the observed-to-expected frequency of mutations, we categorized 34 IDRs in 20 proteins (DDX3X, KIT, RB1, etc.) as intolerant to mutation. Finally, using statistical analysis and a machine learning approach, we demonstrate that mutation-intolerant IDRs carry a distinct signature of functional features. Our study presents a novel approach to assign functional importance to IDRs by leveraging the wealth of available genetic data, which will aid in a deeper understating of the role of IDRs in biological processes and disease mechanisms.

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Section: Discussionmentioning

confidence: 99%

Characterization of intrinsically disordered regions in proteins informed by human genetic diversity

et al. 2022

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“…Disorder domains are characterized by high instability, and substitutions in this region can change the protein conformation. Recent studies have demonstrated that around 20% of mutations in cancers are located in these regions, causing abnormalities of protein conformations and func-tions [22]. Mutations in KMT2C in diffuse GC are associated with epithelial-mesenchymal transition (EMT) and acquisition of the mesenchymal phenotype by cells and are also markers of a poor prognosis [23].…”

Section: Discussionmentioning

confidence: 99%

Mutations in Epigenetic Regulation Genes in Gastric Cancer

Немцова

Калинкин

Kuznetsova

et al. 2021

Cancers

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We have performed mutational profiling of 25 genes involved in epigenetic processes on 135 gastric cancer (GC) samples. In total, we identified 79 somatic mutations in 49/135 (36%) samples. The minority (n = 8) of mutations was identified in DNA methylation/demethylation genes, while the majority (n = 41), in histone modifier genes, among which mutations were most commonly found in KMT2D and KMT2C. Somatic mutations in KMT2D, KMT2C, ARID1A and CHD7 were mutually exclusive (p = 0.038). Mutations in ARID1A were associated with distant metastases (p = 0.03). The overall survival of patients in the group with metastases and in the group with tumors with signet ring cells was significantly reduced in the presence of mutations in epigenetic regulation genes (p = 0.036 and p = 0.041, respectively). Separately, somatic mutations in chromatin remodeling genes correlate with low survival rate of patients without distant metastasis (p = 0.045) and in the presence of signet ring cells (p = 0.0014). Our results suggest that mutations in epigenetic regulation genes may be valuable clinical markers and deserve further exploration in independent cohorts.

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“…Transient protein stabilization may also be due to sequestration or inactivation of the kinase(s) phosphorylating the degron, a phosphorylation that is essential for E3 ligase recognition. During activation of Wnt/LRP6 signaling, the kinase GSK-β which phosphorylates β-catenin, and FbXW7 substrates, such as c-Myc, are sequestered, resulting in the stabilization of β-catenin, c-Myc, and other critical tumor-promoting regulators [ 44 ].…”

Section: Evading Recognition I: Protein Stabilization Due To Lacking or Mutated Degradation Signalsmentioning

confidence: 99%

From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization

Ahmad

Oknin-Vaisman

Bitman-Lotan

et al. 2021

Cells

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A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by the substrate-recognition enzyme, E3 ubiquitin ligase. Stabilization may also result from the inactivation of the enzymatic machinery that mediates the degradation of oncoproteins. Importantly, inactivation in cancer of E3 enzymes that regulates the physiological degradation of oncoproteins, results in tumor cells that accumulate multiple active oncoproteins with prolonged half-lives, leading to the development of “degradation-resistant” cancer cells. In addition, specific sequences may enable ubiquitinated proteins to evade degradation at the 26S proteasome. While the ubiquitin-proteasome pathway was originally discovered as central for protein degradation, in cancer cells a ubiquitin-dependent protein stabilization pathway actively translates transient mitogenic signals into long-lasting protein stabilization and enhances the activity of key oncoproteins. A central enzyme in this pathway is the ubiquitin ligase RNF4. An intimate link connects protein stabilization with tumorigenesis in experimental models as well as in the clinic, suggesting that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer. In this review, we highlight old observations and recent advances in our knowledge regarding protein stabilization.

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Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies

Cited by 32 publications

References 118 publications

Characterization of intrinsically disordered regions in proteins informed by human genetic diversity

Characterization of intrinsically disordered regions in proteins informed by human genetic diversity

Mutations in Epigenetic Regulation Genes in Gastric Cancer

From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization

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