| Autor: |
Güllülü Ö; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Mayer BE; Computational Biology & Simulation, Technische Universität Darmstadt, 64287 Darmstadt, Germany., Toplek FB; Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy. |
| Jazyk: |
angličtina |
| Zdroj: |
International journal of molecular sciences [Int J Mol Sci] 2024 Jan 28; Vol. 25 (3). Date of Electronic Publication: 2024 Jan 28. |
| DOI: |
10.3390/ijms25031606 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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