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BRAT1 links Integrator and defective RNA processing with neurodegeneration
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SYSNO ASEP 0566109 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title BRAT1 links Integrator and defective RNA processing with neurodegeneration Author(s) Cihlářová, Zuzana (UMG-J)
Kubovčiak, Jan (UMG-J)
Sobol, Margaryta (UMG-J) RID
Krejčíková, Kateřina (UMG-J)
Šáchová, Jana (UMG-J)
Kolář, Michal (UMG-J) RID, ORCID
Staněk, David (UMG-J) RID
Bařinka, Cyril (BTO-N) RID, ORCID
Yoon, G. (CA)
Caldecott, Keith (UMG-J)
Hanzlíková, Hana (UMG-J) RIDNumber of authors 11 Article number 5026 Source Title Nature Communications. - : Nature Publishing Group
Roč. 13, č. 1 (2022)Number of pages 14 s. Publication form Online - E Language eng - English Country GB - United Kingdom Keywords Multifocal seizure syndromelethal ; Lethal neonatal regidity ; Histone messenger-RNAS ; Transcription ; Complex ; Association ; Disruption ; Mutation Subject RIV EB - Genetics ; Molecular Biology OECD category Cell biology R&D Projects GA22-00885S GA ČR - Czech Science Foundation (CSF) GA21-04132S GA ČR - Czech Science Foundation (CSF) EF16_019/0000785 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018129 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0016045 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure Czech-BioImaging II - 90129 - Ústav molekulární genetiky AV ČR, v. v. i. Method of publishing Open access Institutional support UMG-J - RVO:68378050 ; BTO-N - RVO:86652036 UT WOS 000845881900001 DOI 10.1038/s41467-022-32763-6 Annotation Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, have been associated with neurodevelopmental and neurodegenerative disorders characterized by heterogeneous phenotypes with varying levels of clinical severity. However, the underlying molecular mechanisms of disease pathology remain poorly understood. Here, we show that BRAT1 tightly interacts with INTS9/INTS11 subunits of the Integrator complex that processes 3' ends of various noncoding RNAs and pre-mRNAs. We find that Integrator functions are disrupted by BRAT1 deletion. In particular, defects in BRAT1 impede proper 3' end processing of UsnRNAs and snoRNAs, replication-dependent histone pre-mRNA processing, and alter the expression of protein-coding genes. Importantly, impairments in Integrator function are also evident in patient-derived cells from BRAT1 related neurological disease. Collectively, our data suggest that defects in BRAT1 interfere with proper Integrator functions, leading to incorrect expression of RNAs and proteins, resulting in neurodegeneration. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2023 Electronic address https://www.nature.com/articles/s41467-022-32763-6
Number of the records: 1