Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms.

Autor:	Kalani L; Department of Biochemistry and Microbiology, University of Victoria, 3800 Finnerty Rd, Victoria, BC V8W 2Y2, Canada., Kim BH; Department of Biochemistry and Microbiology, University of Victoria, 3800 Finnerty Rd, Victoria, BC V8W 2Y2, Canada., de Chavez AR; Department of Biology, University of Victoria, 3800 Finnerty Rd, Victoria, BC V8W 2Y2, Canada., Roemer A; Departments of Oncology and Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Ave, Edmonton, AB T6G 2H7, Canada., Mikhailov A; Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St, Toronto, ON M5T 1R8, Canada., Merritt JK; Vanderbilt Kennedy Center, Departments of Pediatrics, Pharmacology, and Special Education, Vanderbilt University Medical Center and Vanderbilt University, 1211 Medical Center Dr, Nashville, TN 37232, United States., Good KV; Department of Biochemistry and Microbiology, University of Victoria, 3800 Finnerty Rd, Victoria, BC V8W 2Y2, Canada.; Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St, Toronto, ON M5T 1R8, Canada., Chow RL; Department of Biology, University of Victoria, 3800 Finnerty Rd, Victoria, BC V8W 2Y2, Canada., Delaney KR; Department of Biology, University of Victoria, 3800 Finnerty Rd, Victoria, BC V8W 2Y2, Canada., Hendzel MJ; Departments of Oncology and Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Ave, Edmonton, AB T6G 2H7, Canada., Zhou Z; Department of Genetics, Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104, United States., Neul JL; Vanderbilt Kennedy Center, Departments of Pediatrics, Pharmacology, and Special Education, Vanderbilt University Medical Center and Vanderbilt University, 1211 Medical Center Dr, Nashville, TN 37232, United States., Vincent JB; Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St, Toronto, ON M5T 1R8, Canada.; Institute of Medical Science, University of Toronto, 27 King's College Cir, Toronto, ON M5S 1A8, Canada.; Department of Psychiatry, University of Toronto, 27 King College Cir, Toronto, ON M5T 1R8, Canada., Ausió J; Department of Biochemistry and Microbiology, University of Victoria, 3800 Finnerty Rd, Victoria, BC V8W 2Y2, Canada.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2024 Nov 05; Vol. 33 (21), pp. 1833-1845.
DOI:	10.1093/hmg/ddae119
Abstrakt:	Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms. (© The Author(s) 2024. Published by Oxford University Press.)
Databáze:	MEDLINE
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