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.

Department of Pediatrics Division of Clinical and Metabolic Genetics The Hospital for Sick Children University of Toronto Toronto ON M5G 1X8 Canada

Faculty of Science Charles University Prague 128 43 Prague 2 Czech Republic

Genome Damage and Stability Centre School of Life Sciences University of Sussex Falmer Brighton BN1 9RQ UK

Laboratory of Genome Dynamics Institute of Molecular Genetics of the Czech Academy of Sciences 142 20 Prague 4 Czech Republic

Laboratory of Genomics and Bioinformatics Institute of Molecular Genetics of the Czech Academy of Sciences 142 20 Prague 4 Czech Republic

Laboratory of RNA Biology Institute of Molecular Genetics of the Czech Academy of Sciences 142 20 Prague 4 Czech Republic

Laboratory of Structural biology Institute of Biotechnology of the Czech Academy of Sciences BIOCEV 252 50 Vestec Czech Republic

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Dynamic interaction of spliceosomal snRNPs with coilin explains Cajal body characteristics

Coilin and Cajal bodies