| 2017 |
TIRR (NUDT16L1) directly binds the tandem Tudor domain of 53BP1 and masks its H4K20me2 histone methyl-lysine binding motif, preventing 53BP1 recruitment to DNA double-strand breaks. Upon DNA damage, ATM phosphorylates 53BP1 and recruits RIF1 to dissociate the 53BP1-TIRR complex. Overexpression of TIRR impedes 53BP1 localization to DSBs, while depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction. |
Co-immunoprecipitation, overexpression/depletion functional assays, live-cell imaging of DSB foci |
Nature |
High |
28241136
|
| 2018 |
Crystal structure (1.76 Å) of TIRR in complex with the 53BP1 tandem Tudor domain reveals that the N-terminal region (residues 10–24) and the L8-loop of TIRR interact with 53BP1 Tudor through three loops (L1, L3, L1'), blocking the H4K20me2-binding surface. A TIRR-specific histidine (H106), absent from the homolog NUDT16, is essential for 53BP1 Tudor binding; mutations mimicking TIRR binding modules restore disrupted NUDT16-53BP1 Tudor interaction. |
X-ray crystallography, site-directed mutagenesis, binding assays |
Nature communications |
High |
29844495
|
| 2018 |
X-ray crystal structure of TIRR bound to 53BP1 tandem Tudor domain reveals that an essential TIRR arginine residue is central to an intricate binding area that blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of-function mutation abolishing TIRR-mediated regulation renders 53BP1 hyperactive at DSBs. TIRR-interacting RNA molecules relieve this inhibition, providing proof-of-principle of RNA-triggered 53BP1 recruitment to DSBs. |
X-ray crystallography, site-directed mutagenesis, cell-based DSB foci assays, RNA binding assays |
Nature structural & molecular biology |
High |
29967538
|
| 2018 |
Crystal structure of TIRR–53BP1 tandem Tudor domain complex shows three TIRR loops masking the methylated lysine-binding pocket of 53BP1 TTD, competing with histone H4K20 methylation. Key interaction residues were mapped and their mutation abolishes complex formation. NUDT16 does not directly interact with 53BP1 due to absence of key binding residues. TIRR suppresses relocation of 53BP1 to DNA lesions and 53BP1-dependent DNA damage repair. |
X-ray crystallography, site-directed mutagenesis, Co-IP, DSB repair assays |
Nature communications |
High |
30002377
|
| 2021 |
TIRR inhibits complex formation between the Tudor domain of 53BP1 and dimethylated p53 (K382me2), thereby suppressing p53 transcriptional activation of target genes. Loss of TIRR causes an aberrant increase in p53 gene transactivation, affecting p53-mediated cell-fate programs. TIRR depletion is selectively not tolerated in p53-proficient tumors. |
Biochemical binding assays (Tudor domain–K382me2 p53 interaction), gene expression analysis upon TIRR loss, cell viability assays |
Molecular cell |
High |
33961797
|
| 2022 |
RNA with a hairpin secondary structure transcribed at DSBs by RNA polymerase II promotes TIRR/53BP1 complex dissociation. This hairpin RNA binds to the same residues on TIRR as 53BP1, providing the mechanistic basis for RNA-driven complex separation after DNA damage. |
RNA binding assays, mutagenesis mapping of RNA-TIRR interaction surface, cell-based TIRR/53BP1 dissociation assays, RNA polymerase II inhibition |
Cell reports |
Medium |
36288694
|
| 2024 |
NEAT1 long non-coding RNA (specifically the short isoform NEAT1_1, enriched in G1 phase) is the primary RNA partner of TIRR within cells, identified by iCLIP. NEAT1_1 binding destabilizes the TIRR/53BP1 complex, promoting 53BP1 function in a cell-cycle-dependent manner. TDP-43 modulates the TIRR/53BP1 complex by promoting NEAT1_1 production. |
iCLIP (individual-nucleotide resolution UV crosslinking and immunoprecipitation), Co-IP, cell-cycle synchronization, TDP-43 functional assays |
Nature communications |
Medium |
39349456
|
| 2024 |
DTX3L ubiquitinates TIRR at lysine 187, facilitating XPO1-mediated nuclear export and subsequent degradation of TIRR upon DNA damage. This relieves TIRR-mediated inhibition of 53BP1, regulating NHEJ pathway activity and PARP inhibitor sensitivity. DTX3L overexpression (as in prostate cancers) decreases TIRR levels, impairs HR, and induces chromosomal instability. |
Ubiquitination assays, nuclear export inhibition (XPO1 inhibitor), site-directed mutagenesis (K187), co-immunoprecipitation, cellular fractionation, PARP inhibitor sensitivity assays |
Nature communications |
High |
39632881
|
| 2024 |
TIRR selectively binds a subset of mRNAs in response to DNA damage and interacts with the nuclear export protein Exportin-1 (XPO1/CRM1) through a nuclear export signal. TIRR and TIRR-bound RNA co-localize with processing bodies (P-bodies); TIRR depletion results in nuclear RNA retention and impaired P-body formation, linking TIRR's RNA-binding activity to mRNA nuclear export and storage during the DDR. |
RNA immunoprecipitation, co-immunoprecipitation with XPO1, fluorescence microscopy (P-body co-localization), TIRR depletion with mRNA export/P-body formation readouts |
Nucleic acids research |
Medium |
39119906
|
| 2024 |
NUDT16L1 localizes to mitochondria in colon cancer cells, where it prevents mitochondrial DNA leakage upon ferroptosis induction. It promotes ferroptosis insensitivity by binding directly to NAD-capped RNAs and indirectly enhancing expression of ferroptosis repressor and mitochondrial genes through MALAT1. |
Subcellular fractionation/mitochondrial localization, NAD-capped RNA binding assays, NUDT16L1 overexpression/knockdown with ferroptosis assays, transgenic mouse model |
Redox biology |
Medium |
39317106
|
| 2024 |
Deletion of TIRR in mice selectively activates p53, protecting against cancer but causing systemic metabolic imbalance (overweight, insulin resistance). These metabolic and oncoprotective effects are dependent on p53. Tissue-specific models indicate glucose homeostasis is regulated primarily by TIRR expression in adipose tissue, and orexigenesis by TIRR expression in the CNS. |
Conditional/tissue-specific mouse knockout models, metabolic phenotyping, p53 deletion epistasis |
Cell reports |
Medium |
38861384
|
| 2026 |
EGR1 transcription factor directly binds the promoter of NUDT16L1 and activates its expression, establishing NUDT16L1 as a downstream effector of EGR1. Overexpression of NUDT16L1 alone reduces ROS and prevents cell death in spermatogonial stem cells under oxidative stress; silencing NUDT16L1 abolishes EGR1's protective effects against testicular ischemia-reperfusion injury in mice. |
Chromatin immunoprecipitation (ChIP), luciferase reporter assay, NUDT16L1 overexpression/knockdown with ROS/apoptosis readouts, mouse testicular IR injury model |
Cell biology international |
Medium |
41521514
|