Disruption of pathways regulated by Integrator complex in Galloway-Mowat syndrome due to WDR73 mutations.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
08 03 2021
08 03 2021
Historique:
received:
05
05
2020
accepted:
11
02
2021
entrez:
9
3
2021
pubmed:
10
3
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Several studies have reported WDR73 mutations to be causative of Galloway-Mowat syndrome, a rare disorder characterised by the association of neurological defects and renal-glomerular disease. In this study, we demonstrate interaction of WDR73 with the INTS9 and INTS11 components of Integrator, a large multiprotein complex with various roles in RNA metabolism and transcriptional control. We implicate WDR73 in two Integrator-regulated cellular pathways; namely, the processing of uridylate-rich small nuclear RNAs (UsnRNA), and mediating the transcriptional response to epidermal growth factor stimulation. We also show that WDR73 suppression leads to altered expression of genes encoding cell cycle regulatory proteins. Altogether, our results suggest that a range of cellular pathways are perturbed by WDR73 loss-of-function, and support the consensus that proper regulation of UsnRNA maturation, transcription initiation and cell cycle control are all critical in maintaining the health of post-mitotic cells such as glomerular podocytes and neurons, and preventing degenerative disease.
Identifiants
pubmed: 33686175
doi: 10.1038/s41598-021-84472-7
pii: 10.1038/s41598-021-84472-7
pmc: PMC7940485
doi:
Substances chimiques
Proteins
0
WDR73 protein, human
0
Endoribonucleases
EC 3.1.-
IntS9 protein, human
EC 3.1.-
INTS11 protein, human
EC 3.1.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5388Références
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