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BRAT1 links Integrator and defective RNA processing with neurodegeneration

Author

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  • Zuzana Cihlarova

    (Laboratory of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences
    Charles University in Prague)

  • Jan Kubovciak

    (Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Margarita Sobol

    (Laboratory of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Katerina Krejcikova

    (Laboratory of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Jana Sachova

    (Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Michal Kolar

    (Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences)

  • David Stanek

    (Laboratory of RNA Biology, Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Cyril Barinka

    (Laboratory of Structural biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV)

  • Grace Yoon

    (University of Toronto)

  • Keith W. Caldecott

    (Laboratory of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences
    University of Sussex, Falmer)

  • Hana Hanzlikova

    (Laboratory of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences
    University of Sussex, Falmer)

Abstract

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.

Suggested Citation

  • Zuzana Cihlarova & Jan Kubovciak & Margarita Sobol & Katerina Krejcikova & Jana Sachova & Michal Kolar & David Stanek & Cyril Barinka & Grace Yoon & Keith W. Caldecott & Hana Hanzlikova, 2022. "BRAT1 links Integrator and defective RNA processing with neurodegeneration," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32763-6
    DOI: 10.1038/s41467-022-32763-6
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