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

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that inhibits 53BP1's access to DNA double-strand breaks (DSBs).
• Understanding the regulatory mechanisms of DNA repair pathways is crucial for disease research.

Purpose of the Study:

• To identify the RNA molecules that directly bind to TIRR.
• To elucidate the role of NEAT1 in regulating the TIRR/53BP1 interaction and DNA repair.
• To investigate the influence of TDP-43 on this pathway.

Main Methods:

• Individual-nucleotide resolution crosslinking followed by immunoprecipitation (iCLIP) to identify TIRR-bound RNAs.
• Analysis of RNA-binding motifs and protein complex interactions.
• Cell cycle synchronization and analysis.

Main Results:

• The long non-coding RNA NEAT1, specifically its short isoform NEAT1_1, was identified as the primary RNA partner for TIRR.
• High affinity binding of TIRR to NEAT1_1 is mediated by G-rich motifs.
• NEAT1_1 binding destabilizes the TIRR/53BP1 complex, promoting 53BP1 function in DNA repair.
• NEAT1_1 expression is enriched in the G1 phase, making TIRR's inhibitory function cell cycle-dependent.
• TDP-43 promotes NEAT1_1 production, thereby modulating the TIRR/53BP1 complex.

Conclusions:

• NEAT1_1 acts as a crucial regulator of DNA double-strand break repair by modulating TIRR's interaction with 53BP1.
• The cell cycle-dependent regulation of 53BP1 function by NEAT1_1 has significant implications for understanding DNA repair fidelity.
• Dysregulation of NEAT1_1 and its interacting factors, including TDP-43, may contribute to various diseases.