Journal Article

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

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

2024

Overview

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. TIRR interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. Here, the authors show that the lncRNA NEAT1, regulated by TDP-43, destabilizes the TIRR/53BP1 complex in G1, promoting 53BP1’s function in DSB repair and p53 transactivation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/89 / 14 / 14/32 / 14/63 / 38 / 49/47 / 49/88 / 49/90 / 49/91 / 631/337 / 631/337/1427 / Cell cycle / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded / DNA damage / DNA Repair / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / G1 phase / Genomic Instability / HEK293 Cells / Humanities and Social Sciences / Humans / multidisciplinary / Neurodegenerative diseases / p53 Protein / Protein Binding / Ribonucleic acid / RNA / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / RNA-binding protein / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Tumor Suppressor p53-Binding Protein 1 - genetics / Tumor Suppressor p53-Binding Protein 1 - metabolism / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Yeast