BRAT1 links Integrator and defective RNA processing with neurodegeneration

0566109 - ÚMG 2023 RIV GB eng J - Journal Article
Cihlářová, Zuzana - Kubovčiak, Jan - Sobol, Margaryta - Krejčíková, Kateřina - Šáchová, Jana - Kolář, Michal - Staněk, David - Bařinka, Cyril - Yoon, G. - Caldecott, Keith - Hanzlíková, Hana
BRAT1 links Integrator and defective RNA processing with neurodegeneration.
Nature Communications. Roč. 13, č. 1 (2022), č. článku 5026. E-ISSN 2041-1723
R&D Projects: GA ČR GA22-00885S; GA ČR GA21-04132S; GA MŠMT(CZ) EF16_019/0000785; GA MŠMT(CZ) LM2018129; GA MŠMT(CZ) EF18_046/0016045; GA MŠMT(CZ) ED1.1.00/02.0109
Research Infrastructure: Czech-BioImaging II - 90129
Institutional support: RVO:68378050 ; RVO:86652036
Keywords : Multifocal seizure syndromelethal * Lethal neonatal regidity * Histone messenger-RNAS * Transcription * Complex * Association * Disruption * Mutation
OECD category: Cell biology; Cell biology (BTO-N)
Impact factor: 16.6, year: 2022
Method of publishing: Open access
https://www.nature.com/articles/s41467-022-32763-6

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.
Permanent Link: https://hdl.handle.net/11104/0337543