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NEAT1 modulates the TIRR/53BP1 complex to maintain genome integrity

Author

Listed:
  • Susan Kilgas

    (Harvard Medical School)

  • Aleem Syed

    (Harvard Medical School)

  • Patrick Toolan-Kerr

    (1 Midland Road
    5 Cutcombe Rd)

  • Michelle L. Swift

    (Harvard Medical School)

  • Shrabasti Roychoudhury

    (Harvard Medical School)

  • Aniruddha Sarkar

    (Harvard Medical School)

  • Sarah Wilkins

    (Harvard Medical School
    333 Cedar St)

  • Mikayla Quigley

    (Harvard Medical School
    300 Longwood Ave)

  • Anna R. Poetsch

    (Tatzberg 47-49)

  • Maria Victoria Botuyan

    (Mayo Clinic)

  • Gaofeng Cui

    (Mayo Clinic)

  • Georges Mer

    (Mayo Clinic)

  • Jernej Ule

    (1 Midland Road
    5 Cutcombe Rd)

  • Pascal Drané

    (Harvard Medical School)

  • Dipanjan Chowdhury

    (Harvard Medical School)

Abstract

Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying the long non-coding RNA NEAT1 as the primary RNA partner. The high affinity of TIRR for NEAT1 is due to prevalent G-rich motifs in the short isoform (NEAT1_1) region of NEAT1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1’s function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1’s function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting the production of the NEAT1 short isoform, NEAT1_1. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases.

Suggested Citation

  • Susan Kilgas & Aleem Syed & Patrick Toolan-Kerr & Michelle L. Swift & Shrabasti Roychoudhury & Aniruddha Sarkar & Sarah Wilkins & Mikayla Quigley & Anna R. Poetsch & Maria Victoria Botuyan & Gaofeng C, 2024. "NEAT1 modulates the TIRR/53BP1 complex to maintain genome integrity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52862-w
    DOI: 10.1038/s41467-024-52862-w
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