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

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 Cui, Georges Mer, Jernej Ule, Pascal Drané () and Dipanjan Chowdhury ()
Additional contact information
Susan Kilgas: Harvard Medical School
Aleem Syed: Harvard Medical School
Patrick Toolan-Kerr: 1 Midland Road
Michelle L. Swift: Harvard Medical School
Shrabasti Roychoudhury: Harvard Medical School
Aniruddha Sarkar: Harvard Medical School
Sarah Wilkins: Harvard Medical School
Mikayla Quigley: Harvard Medical School
Anna R. Poetsch: Tatzberg 47-49
Maria Victoria Botuyan: Mayo Clinic
Gaofeng Cui: Mayo Clinic
Georges Mer: Mayo Clinic
Jernej Ule: 1 Midland Road
Pascal Drané: Harvard Medical School
Dipanjan Chowdhury: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52862-w

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