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Linking gene fusions to bone marrow failure and malignant transformation in Dyskeratosis Congenita

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, 25 (3)
doi: 10.3390/ijms25031606
Artikel, Bibliographie

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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: Bibliographie
Titel: Linking gene fusions to bone marrow failure and malignant transformation in Dyskeratosis Congenita
Sprache: Englisch
Publikationsjahr: 28 Januar 2024
Ort: 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: 10.3390/ijms25031606
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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.

Freie Schlagworte: Dyskeratosis congenita, telomere disorders, bone marrow failure, genomic instability, gene fusions, RNA-Seq, polyampholytes
ID-Nummer: Artikel-ID: 1606
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: 14 Mai 2024 06:49
Letzte Änderung: 14 Mai 2024 06:49
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