Güllülü, Ömer ; Mayer, Benjamin E. ; Toplek, Fran Bačić (2024)
Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita.
In: International Journal of Molecular Sciences, 2024, 25 (3)
doi: 10.26083/tuprints-00027184
Artikel, Zweitveröffentlichung, Verlagsversion
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Kurzbeschreibung (Abstract)
Dyskeratosis Congenita (DC) is a multisystem disorder intrinsically associated with telomere dysfunction, leading to bone marrow failure (BMF). Although the pathology of DC is largely driven by mutations in telomere-associated genes, the implications of gene fusions, which emerge due to telomere-induced genomic instability, remain unexplored. We meticulously analyzed gene fusions in RNA-Seq data from DC patients to provide deeper insights into DC’s progression. The most significant DC-specific gene fusions were subsequently put through in silico assessments to ascertain biophysical and structural attributes, including charge patterning, inherent disorder, and propensity for self-association. Selected candidates were then analyzed using deep learning-powered structural predictions and molecular dynamics simulations to gauge their potential for forming higher-order oligomers. Our exploration revealed that genes participating in fusion events play crucial roles in upholding genomic stability, facilitating hematopoiesis, and suppressing tumors. Notably, our analysis spotlighted a particularly disordered polyampholyte fusion protein that exhibits robust higher-order oligomerization dynamics. To conclude, this research underscores the potential significance of several high-confidence gene fusions in the progression of BMF in DC, particularly through the dysregulation of genomic stability, hematopoiesis, and tumor suppression. Additionally, we propose that these fusion proteins might hold a detrimental role, specifically in inducing proteotoxicity-driven hematopoietic disruptions.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Güllülü, Ömer ; Mayer, Benjamin E. ; Toplek, Fran Bačić |
| Art des Eintrags: | Zweitveröffentlichung |
| Titel: | Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita |
| Sprache: | Englisch |
| Publikationsjahr: | 13 Mai 2024 |
| Ort: | Darmstadt |
| Publikationsdatum der Erstveröffentlichung: | 28 Januar 2024 |
| Ort der Erstveröffentlichung: | Basel |
| Verlag: | MDPI |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | International Journal of Molecular Sciences |
| Jahrgang/Volume einer Zeitschrift: | 25 |
| (Heft-)Nummer: | 3 |
| Kollation: | 19 Seiten |
| DOI: | 10.26083/tuprints-00027184 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/27184 |
| Zugehörige Links: | |
| Herkunft: | Zweitveröffentlichung DeepGreen |
| Kurzbeschreibung (Abstract): | Dyskeratosis Congenita (DC) is a multisystem disorder intrinsically associated with telomere dysfunction, leading to bone marrow failure (BMF). Although the pathology of DC is largely driven by mutations in telomere-associated genes, the implications of gene fusions, which emerge due to telomere-induced genomic instability, remain unexplored. We meticulously analyzed gene fusions in RNA-Seq data from DC patients to provide deeper insights into DC’s progression. The most significant DC-specific gene fusions were subsequently put through in silico assessments to ascertain biophysical and structural attributes, including charge patterning, inherent disorder, and propensity for self-association. Selected candidates were then analyzed using deep learning-powered structural predictions and molecular dynamics simulations to gauge their potential for forming higher-order oligomers. Our exploration revealed that genes participating in fusion events play crucial roles in upholding genomic stability, facilitating hematopoiesis, and suppressing tumors. Notably, our analysis spotlighted a particularly disordered polyampholyte fusion protein that exhibits robust higher-order oligomerization dynamics. To conclude, this research underscores the potential significance of several high-confidence gene fusions in the progression of BMF in DC, particularly through the dysregulation of genomic stability, hematopoiesis, and tumor suppression. Additionally, we propose that these fusion proteins might hold a detrimental role, specifically in inducing proteotoxicity-driven hematopoietic disruptions. |
| Freie Schlagworte: | Dyskeratosis congenita, telomere disorders, bone marrow failure, genomic instability, gene fusions, RNA-Seq, polyampholytes |
| ID-Nummer: | Artikel-ID: 1606 |
| Status: | Verlagsversion |
| URN: | urn:nbn:de:tuda-tuprints-271847 |
| Zusätzliche Informationen: | This article belongs to the Section Molecular Informatics |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Computational Biology and Simulation |
| Hinterlegungsdatum: | 13 Mai 2024 12:53 |
| Letzte Änderung: | 14 Mai 2024 06:49 |
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- Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita. (deposited 13 Mai 2024 12:53) [Gegenwärtig angezeigt]
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