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PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects

Author

Listed:
  • Robert Atkinson

    (Newcastle University)

  • Maria Georgiou

    (Newcastle University)

  • Chunbo Yang

    (Newcastle University)

  • Katarzyna Szymanska

    (University of Leeds)

  • Albert Lahat

    (Durham University)

  • Elton J. R. Vasconcelos

    (University of Leeds)

  • Yanlong Ji

    (Max-Planck-Institute for Multidisciplinary Sciences
    University Medical Center Göttingen)

  • Marina Moya Molina

    (Newcastle University
    Newcells Biotech)

  • Joseph Collin

    (Newcastle University)

  • Rachel Queen

    (Newcastle University)

  • Birthe Dorgau

    (Newcastle University)

  • Avril Watson

    (Newcastle University
    Newcells Biotech)

  • Marzena Kurzawa-Akanbi

    (Newcastle University)

  • Ross Laws

    (Newcastle University)

  • Abhijit Saxena

    (Newcastle University)

  • Chia Shyan Beh

    (Newcastle University)

  • Chileleko Siachisumo

    (Newcastle University)

  • Franziska Goertler

    (University of Bergen)

  • Magdalena Karwatka

    (University of Leeds)

  • Tracey Davey

    (Newcastle University)

  • Chris F. Inglehearn

    (University of Leeds)

  • Martin McKibbin

    (University of Leeds)

  • Reinhard Lührmann

    (Max-Planck-Institute for Multidisciplinary Sciences)

  • David H. Steel

    (Newcastle University)

  • David J. Elliott

    (Newcastle University)

  • Lyle Armstrong

    (Newcastle University)

  • Henning Urlaub

    (Max-Planck-Institute for Multidisciplinary Sciences
    University Medical Center Göttingen
    Georg August University of Göttingen)

  • Robin R. Ali

    (Kings College London)

  • Sushma-Nagaraja Grellscheid

    (Durham University
    University of Bergen)

  • Colin A. Johnson

    (University of Leeds)

  • Sina Mozaffari-Jovin

    (Max-Planck-Institute for Multidisciplinary Sciences
    Mashhad University of Medical Sciences)

  • Majlinda Lako

    (Newcastle University)

Abstract

The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926 A > C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5’-splice site (5’SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5’SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches.

Suggested Citation

  • Robert Atkinson & Maria Georgiou & Chunbo Yang & Katarzyna Szymanska & Albert Lahat & Elton J. R. Vasconcelos & Yanlong Ji & Marina Moya Molina & Joseph Collin & Rachel Queen & Birthe Dorgau & Avril W, 2024. "PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47253-0
    DOI: 10.1038/s41467-024-47253-0
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    References listed on IDEAS

    as
    1. Adriana Buskin & Lili Zhu & Valeria Chichagova & Basudha Basu & Sina Mozaffari-Jovin & David Dolan & Alastair Droop & Joseph Collin & Revital Bronstein & Sudeep Mehrotra & Michael Farkas & Gerrit Hilg, 2018. "Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa," Nature Communications, Nature, vol. 9(1), pages 1-19, December.
    2. Cyrille Girard & Cindy L. Will & Jianhe Peng & Evgeny M. Makarov & Berthold Kastner & Ira Lemm & Henning Urlaub & Klaus Hartmuth & Reinhard Lührmann, 2012. "Post-transcriptional spliceosomes are retained in nuclear speckles until splicing completion," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    3. Sarah Djebali & Carrie A. Davis & Angelika Merkel & Alex Dobin & Timo Lassmann & Ali Mortazavi & Andrea Tanzer & Julien Lagarde & Wei Lin & Felix Schlesinger & Chenghai Xue & Georgi K. Marinov & Jaina, 2012. "Landscape of transcription in human cells," Nature, Nature, vol. 489(7414), pages 101-108, September.
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