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

Publication Type:

Journal Article

Authors:

Kilgas, Susan; Syed, Aleem; Toolan-Kerr, Patrick; Swift, Michelle L; Roychoudhury, Shrabasti; Sarkar, Aniruddha; Wilkins, Sarah; Quigley, Mikayla; Poetsch, Anna R; Botuyan, Maria Victoria; Cui, Gaofeng; Mer, Georges; Ule, Jernej; Drané, Pascal; Chowdhury, Dipanjan

Source:

Nat Commun, Volume 15, Issue 1, p.8438 (2024)

Keywords:

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

Abstract:

<p>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&#39;s function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1&#39;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.</p>

PDB: 
8U3S
Detector: 
EIGER
Beamline: 
24-ID-E