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

Nat Commun. 2024 Sep 30;15(1):8438. doi: 10.1038/s41467-024-52862-w.

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.

MeSH terms

  • DNA Breaks, Double-Stranded
  • DNA Repair
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Genomic Instability
  • HEK293 Cells
  • Humans
  • Protein Binding
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor p53-Binding Protein 1* / genetics
  • Tumor Suppressor p53-Binding Protein 1* / metabolism

Substances

  • Tumor Suppressor p53-Binding Protein 1
  • TP53BP1 protein, human
  • NEAT1 long non-coding RNA, human
  • RNA-Binding Proteins
  • DNA-Binding Proteins
  • RNA, Long Noncoding
  • TARDBP protein, human
  • NUDT16L1 protein, human
  • Tumor Suppressor Protein p53