8U3S

Structure of human TIRR in complex with VHH4 nanobody

Summary for 8U3S

• Entry DOI: 10.2210/pdb8u3s/pdb
• Descriptor: Tudor-interacting repair regulator protein, Nanobody (3 entities in total)
• Functional Keywords: tirr, nanobody, rna, 53bp1, p53, neat1, dna damage response, dna double-strand break repair, cell cycle, rna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 36775.03

Authors

Botuyan, M.V.,Mer, G. (deposition date: 2023-09-08, release date: 2024-09-04, Last modification date: 2024-10-16)

Primary citation

Kilgas, S.,Syed, A.,Toolan-Kerr, P.,Swift, M.L.,Roychoudhury, S.,Sarkar, A.,Wilkins, S.,Quigley, M.,Poetsch, A.R.,Botuyan, M.V.,Cui, G.,Mer, G.,Ule, J.,Drane, P.,Chowdhury, D.
NEAT1 modulates the TIRR/53BP1 complex to maintain genome integrity.
Nat Commun, 15:8438-8438, 2024

PubMed 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.

PubMed: 39349456
DOI: 10.1038/s41467-024-52862-w

Experimental method

X-RAY DIFFRACTION (1.85 Å)