TIRR regulates mRNA export and association with P-bodies in response to DNA damage.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

RNA, Messenger*/metabolism ; RNA, Messenger*/genetics ; DNA Damage* ; RNA Transport* ; RNA-Binding Proteins*/metabolism ; RNA-Binding Proteins*/genetics; Humans ; Karyopherins/metabolism ; Karyopherins/genetics ; Exportin 1 Protein ; Active Transport, Cell Nucleus ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; DNA Breaks, Double-Stranded ; Cell Nucleus/metabolism ; Cell Nucleus/genetics ; DNA Repair ; Nuclear Export Signals/genetics ; RNA Processing, Post-Transcriptional ; DEAD-box RNA Helicases

To ensure the integrity of our genetic code, a coordinated network of signalling and repair proteins, known as the DNA damage response (DDR), detects and repairs DNA insults, the most toxic being double-strand breaks (DSBs). Tudor interacting repair regulator (TIRR) is a key factor in DSB repair, acting through its interaction with p53 binding protein 1 (53BP1). TIRR is also an RNA binding protein, yet its role in RNA regulation during the DDR remains elusive. Here, we show that TIRR selectively binds to a subset of messenger RNAs (mRNAs) in response to DNA damage. Upon DNA damage, TIRR interacts with the nuclear export protein Exportin-1 through a nuclear export signal. Furthermore, TIRR plays a crucial role in the modulation of RNA processing bodies (PBs). TIRR itself and TIRR-bound RNA co-localize with PBs, and TIRR depletion results in nuclear RNA retention and impaired PB formation. We also suggest a potential link between TIRR-regulated RNA export and efficient DDR. This work reveals intricate involvement of TIRR in orchestrating mRNA nuclear export and storage within PBs, emphasizing its significance in the regulation of RNA-mediated DDR.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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BVR01670 E P A Cephalosporin Fund; Lee Placito Medical Fund; University of Oxford; BVR01170 United Kingdom CRUK_ Cancer Research UK

0 (RNA, Messenger)
0 (RNA-Binding Proteins)
0 (Karyopherins)
0 (Exportin 1 Protein)
0 (Receptors, Cytoplasmic and Nuclear)
EC 3.6.1.- (DDX39B protein, human)
0 (Nuclear Export Signals)
EC 3.6.4.13 (DEAD-box RNA Helicases)

Date Created: 20240809 Date Completed: 20241111 Latest Revision: 20241113

20241114

PMC11551748

10.1093/nar/gkae688

39119906