de novo MEPCE nonsense variant associated with a neurodevelopmental disorder causes disintegration of 7SK snRNP and enhanced RNA polymerase II activation.

Autor: Schneeberger PE; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Bierhals T; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Neu A; Childrens Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Hempel M; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Kutsche K; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. kkutsche@uke.de.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Aug 29; Vol. 9 (1), pp. 12516. Date of Electronic Publication: 2019 Aug 29.
DOI: 10.1038/s41598-019-49032-0
Abstrakt: In eukaryotes, the elongation phase of transcription by RNA polymerase II (RNAP II) is regulated by the transcription elongation factor b (P-TEFb), composed of Cyclin-T1 and cyclin-dependent kinase 9. The release of RNAP II is mediated by phosphorylation through P-TEFb that in turn is under control by the inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex. The 7SK snRNP consists of the 7SK non-coding RNA and the proteins MEPCE, LARP7, and HEXIM1/2. Biallelic LARP7 loss-of-function variants underlie Alazami syndrome characterized by growth retardation and intellectual disability. We report a boy with global developmental delay and seizures carrying the de novo MEPCE nonsense variant c.1552 C > T/p.(Arg518*). mRNA and protein analyses identified nonsense-mediated mRNA decay to underlie the decreased amount of MEPCE in patient fibroblasts followed by LARP7 and 7SK snRNA downregulation and HEXIM1 upregulation. Reduced binding of HEXIM1 to Cyclin-T1, hyperphosphorylation of the RNAP II C-terminal domain, and upregulated expression of ID2, ID3, MRPL11 and snRNAs U1, U2 and U4 in patient cells are suggestive of enhanced activation of P-TEFb. Flavopiridol treatment and ectopic MEPCE protein expression in patient fibroblasts rescued increased expression of six RNAP II-sensitive genes and suggested a possible repressive effect of MEPCE on P-TEFb-dependent transcription of specific genes.
Databáze: MEDLINE
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