NUDT16L1

Summary

NUDT16L1 (nudix hydrolase 16 like 1, HGNC:28154) is a protein-coding gene on chromosome 16p13.3, encoding Tudor-interacting repair regulator protein (Q9BRJ7). Key regulator of TP53BP1 required to stabilize TP53BP1 and regulate its recruitment to chromatin. It is a selective cancer dependency (DepMap: 12.8% of cell lines).

Enables snoRNA binding activity. Involved in negative regulation of double-strand break repair via nonhomologous end joining. Located in nucleus.

Source: NCBI Gene 84309 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 53 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 12.8% of screened cell lines
• MANE Select transcript: NM_032349

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28154
Approved symbol	NUDT16L1
Name	nudix hydrolase 16 like 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	SDOS, TIRR
Ensembl gene	ENSG00000168101
Ensembl biotype	protein_coding
OMIM	617338
Entrez	84309

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000304301, ENST00000405142, ENST00000586252, ENST00000586536, ENST00000590460, ENST00000860911, ENST00000860912, ENST00000924884

RefSeq mRNA: 6 — MANE Select: NM_032349 NM_001193452, NM_001370585, NM_001370586, NM_001370587, NM_001370588, NM_032349

CCDS: CCDS10519, CCDS59257, CCDS92097

Canonical transcript exons

ENST00000304301 — 3 exons

Exon	Start	End
ENSE00001145597	4693978	4694238
ENSE00003978202	4693562	4693879
ENSE00003978203	4694958	4695844

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 94.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.3194 / max 115.0125, expressed in 1807 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152490	13.7135	1802
152489	2.6059	1444

Top tissues by expression

139 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	94.42	gold quality
heart left ventricle	UBERON:0002084	93.08	gold quality
right adrenal gland cortex	UBERON:0035827	92.81	gold quality
right adrenal gland	UBERON:0001233	92.80	gold quality
apex of heart	UBERON:0002098	92.42	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.15	gold quality
granulocyte	CL:0000094	92.07	gold quality
putamen	UBERON:0001874	91.99	gold quality
left adrenal gland	UBERON:0001234	91.95	gold quality
right lobe of liver	UBERON:0001114	91.92	gold quality
nucleus accumbens	UBERON:0001882	91.87	gold quality
left adrenal gland cortex	UBERON:0035825	91.83	gold quality
pituitary gland	UBERON:0000007	91.69	gold quality
right atrium auricular region	UBERON:0006631	91.56	gold quality
right frontal lobe	UBERON:0002810	91.50	gold quality
anterior cingulate cortex	UBERON:0009835	91.49	gold quality
caudate nucleus	UBERON:0001873	91.35	gold quality
adenohypophysis	UBERON:0002196	91.35	gold quality
cerebellar hemisphere	UBERON:0002245	91.31	gold quality
cerebellum	UBERON:0002037	91.26	gold quality
Ammon’s horn	UBERON:0001954	91.23	gold quality
cerebellar cortex	UBERON:0002129	91.21	gold quality
heart	UBERON:0000948	91.18	gold quality
metanephros cortex	UBERON:0010533	91.13	gold quality
substantia nigra	UBERON:0002038	90.91	gold quality
adult mammalian kidney	UBERON:0000082	90.90	gold quality
temporal lobe	UBERON:0001871	90.71	gold quality
brain	UBERON:0000955	90.66	gold quality
amygdala	UBERON:0001876	90.65	gold quality
hypothalamus	UBERON:0001898	90.60	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting NUDT16L1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-4298	97.26	66.59	765
HSA-MIR-196B-3P	85.79	67.95	91

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• TIRR is a novel 53BP1-interacting protein that participates in the DNA damage response (PMID:28213517)
• findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1 (PMID:28241136)
• This study elucidates the mechanism by which TIRR recognizes 53BP1 Tudor and functions as a cellular inhibitor of the histone methyl-lysine readers. (PMID:29844495)
• X-ray crystal structures of TIRR and a designer protein bound to 53BP1 now reveal a mechanism in which an intricate binding area centered on an essential TIRR arginine residue blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of-function mutation that abolishes TIRR-mediated regulation in cells renders 53BP1 hyperactive in response to DSBs, highlighting the key inhibitory function of TIRR. (PMID:29967538)
• Data indicate the molecular mechanism underlying Tudor interacting repair regulator (TIRR)-mediated suppression of tumor protein p53 binding protein 1 (53BP1)-dependent DNA damage repair. (PMID:30002377)
• Identification of a small subset of mRNAs responsible for the biogenesis of primary cilium that have been linked to developmental and degenerative diseases, known as ciliopathies, and cancer. SDOS binds and regulates the translation of several of these mRNAs, controlling cilia development. (PMID:30260431)
• TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs. (PMID:33961797)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:103759	ENSDARG00000019503
mus_musculus	Nudt16l1	ENSMUSG00000022516
rattus_norvegicus	Nudt16l1	ENSRNOG00000003224

Paralogs (1): NUDT16 (ENSG00000198585)

Protein

Protein identifiers

Tudor-interacting repair regulator protein — Q9BRJ7 (reviewed: Q9BRJ7)

Alternative names: NUDT16-like protein 1, Protein syndesmos

All UniProt accessions (4): Q9BRJ7, K7EIN2, K7ENA3, W4VSQ8

UniProt curated annotations — full annotation on UniProt →

Function. Key regulator of TP53BP1 required to stabilize TP53BP1 and regulate its recruitment to chromatin. In absence of DNA damage, interacts with the tandem Tudor-like domain of TP53BP1, masking the region that binds histone H4 dimethylated at ‘Lys-20’ (H4K20me2), thereby preventing TP53BP1 recruitment to chromatin and maintaining TP53BP1 localization to the nucleus. Following DNA damage, ATM-induced phosphorylation of TP53BP1 and subsequent recruitment of RIF1 leads to dissociate NUDT16L1/TIRR from TP53BP1, unmasking the tandem Tudor-like domain and allowing recruitment of TP53BP1 to DNA double strand breaks (DSBs). Binds U8 snoRNA.

Subunit / interactions. Homodimer. Interacts with TP53BP1 (via the Tudor-like domain); interaction is abolished following DNA damage and TP53BP1 phosphorylation by ATM. Interacts (via the cytoplasmic part) with SDC4. Interacts with TGFB1I1 and PXN.

Subcellular location. Nucleus.

Similarity. Belongs to the Nudix hydrolase family. TIRR subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BRJ7-1	1	yes
Q9BRJ7-2	2

RefSeq proteins (6): NP_001180381, NP_001357514, NP_001357515, NP_001357516, NP_001357517, NP_115725* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015797	NUDIX_hydrolase-like_dom_sf	Homologous_superfamily
IPR054754	NudT16	Family

Pfam: PF22327

UniProt features (27 total): strand 9, helix 7, turn 3, cross-link 2, mutagenesis site 2, chain 1, region of interest 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3KVH	X-RAY DIFFRACTION	1.7
8U3S	X-RAY DIFFRACTION	1.85
6D0L	X-RAY DIFFRACTION	1.97
5ZCJ	X-RAY DIFFRACTION	2
6CO1	X-RAY DIFFRACTION	2.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BRJ7-F1	93.84	0.88

Antibody-complex structures (SAbDab): 1 — 8U3S

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 10 (required for interaction with tp53bp1)

Post-translational modifications (2): 10, 151

Mutagenesis-validated functional residues (2):

Position	Phenotype
10	abolishes interaction with tp53bp1.
151	still able to interact with tp53bp1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 108 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOBP_SNO_S_RNA_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_DNA_REPAIR, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_DNA_REPAIR, MODULE_331, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DNA_DAMAGE_RESPONSE

GO Biological Process (1): negative regulation of double-strand break repair via nonhomologous end joining (GO:2001033)

GO Molecular Function (3): RNA binding (GO:0003723), snoRNA binding (GO:0030515), protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
double-strand break repair via nonhomologous end joining	1
negative regulation of double-strand break repair	1
regulation of double-strand break repair via nonhomologous end joining	1
nucleic acid binding	1
RNA binding	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

376 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUDT16L1	SDC4	P31431	715
NUDT16L1	PXN	P49023	545
NUDT16L1	TP53BP1	Q12888	528
NUDT16L1	DNM2	P50570	439
NUDT16L1	OR6P1	Q8NGX9	419
NUDT16L1	PTEN	P60484	374
NUDT16L1	SDCBP	O00560	370
NUDT16L1	CCDC97	Q96F63	359
NUDT16L1	FAM228B	P0C875	356
NUDT16L1	OR52B2	Q96RD2	348
NUDT16L1	FBXW9	Q5XUX1	346
NUDT16L1	NUDT13	Q86X67	343
NUDT16L1	CASK	O14936	323
NUDT16L1	TGFB1I1	O43294	314
NUDT16L1	TMEM184C	Q9NVA4	311

IntAct

89 interactions, top by confidence:

A	B	Type	Score
TRAF2	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.720
HNRNPH1	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.670
NTNG1	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.620
PNMA1	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.560
NTAQ1	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.560
NUDT16L1	TRAF4	psi-mi:“MI:0915”(physical association)	0.560
NUDT16L1	IKZF3	psi-mi:“MI:0915”(physical association)	0.560
KRT31	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.560
NUDT16L1	ZRANB1	psi-mi:“MI:0915”(physical association)	0.560
INCA1	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.560
RECK	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.560
NUDT16L1	CABP2	psi-mi:“MI:0915”(physical association)	0.560
NUDT16L1	METTL17	psi-mi:“MI:0915”(physical association)	0.560
HNRNPF	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.560
SMARCD1	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.560
NUDT16L1	NEK6	psi-mi:“MI:0915”(physical association)	0.560
TRIM68	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH2	PLOD2	psi-mi:“MI:0914”(association)	0.530
CRYAB	CCDC85C	psi-mi:“MI:0914”(association)	0.530
TCEAL1	CHEK1	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
VEGFB	LAMB2	psi-mi:“MI:0914”(association)	0.530
LRRK1	NUDT16L1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (131): NUDT16L1 (Two-hybrid), NUDT16L1 (Two-hybrid), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16 (Affinity Capture-MS), TP53BP1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Affinity Capture-MS), NUDT16L1 (Biochemical Activity)

ESM2 similar proteins: A0A1D5PJB7, A1A4Q9, A5YM72, A6NLP5, D3KCC4, I3L5V6, O43292, P10938, Q00973, Q05B52, Q09200, Q10468, Q14623, Q148G5, Q16586, Q2V8X7, Q3SZV0, Q561R2, Q5E9M9, Q5M868, Q5ZL13, Q66H45, Q69ZF3, Q6P3D0, Q6P7A1, Q6P9Z4, Q6SZW1, Q6TEC1, Q6ZPS2, Q7TMC8, Q864R5, Q86TX2, Q8IXI1, Q8N0W3, Q8N3Y3, Q8N6R0, Q8NF37, Q8NI29, Q8TCD5, Q8VBW8

Diamond homologs: A1A4Q9, P0DKY8, Q2V8X7, Q6P3D0, Q6TEC1, Q8VHN8, Q96DE0, Q9BRJ7, Q9IAY5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

53 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

412 predictions. Top by Δscore:

Variant	Effect	Δscore
16:4693877:CTGGT:C	donor_loss	1.0000
16:4693878:TGGTG:T	donor_loss	1.0000
16:4693879:GGTGA:G	donor_loss	1.0000
16:4693880:G:GC	donor_loss	1.0000
16:4693880:G:GG	donor_gain	1.0000
16:4693881:T:G	donor_loss	1.0000
16:4693885:G:GT	donor_gain	1.0000
16:4694236:G:GT	donor_gain	1.0000
16:4693876:GCTG:G	donor_gain	0.9900
16:4693882:GAG:G	donor_loss	0.9900
16:4693976:A:AG	acceptor_gain	0.9900
16:4693977:G:GG	acceptor_gain	0.9900
16:4693977:GATGC:G	acceptor_gain	0.9900
16:4694295:G:GT	donor_gain	0.9900
16:4693977:GA:G	acceptor_gain	0.9800
16:4693977:GAT:G	acceptor_gain	0.9800
16:4694207:GCGCG:G	donor_gain	0.9800
16:4694234:TGGAG:T	donor_loss	0.9800
16:4694237:AGGTG:A	donor_loss	0.9800
16:4694238:GGTGG:G	donor_loss	0.9800
16:4694239:G:T	donor_loss	0.9800
16:4694240:T:A	donor_loss	0.9800
16:4694300:C:T	donor_gain	0.9800
16:4694305:A:G	donor_gain	0.9800
16:4694307:GG:G	donor_gain	0.9800
16:4694308:GG:G	donor_gain	0.9800
16:4694952:GCGCA:G	acceptor_loss	0.9800
16:4694953:C:CA	acceptor_gain	0.9800
16:4694953:CGCA:C	acceptor_loss	0.9800
16:4694954:GCAGG:G	acceptor_loss	0.9800

AlphaMissense

1350 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:4693990:T:C	F56L	0.999
16:4693992:C:A	F56L	0.999
16:4693992:C:G	F56L	0.999
16:4693994:A:T	D57V	0.999
16:4693996:G:T	G58W	0.999
16:4693997:G:A	G58E	0.999
16:4694009:T:C	F62S	0.999
16:4694977:T:A	V145D	0.999
16:4695022:T:C	F160S	0.999
16:4695036:T:C	F165L	0.999
16:4695038:C:A	F165L	0.999
16:4695038:C:G	F165L	0.999
16:4693847:T:C	F41L	0.998
16:4693849:C:A	F41L	0.998
16:4693849:C:G	F41L	0.998
16:4693997:G:T	G58V	0.998
16:4694008:T:C	F62L	0.998
16:4694010:C:A	F62L	0.998
16:4694010:C:G	F62L	0.998
16:4694014:G:T	G64W	0.998
16:4694015:G:A	G64E	0.998
16:4694189:T:C	L122P	0.998
16:4694964:G:C	G141R	0.998
16:4694980:C:A	P146Q	0.998
16:4695061:T:C	L173P	0.998
16:4693810:C:G	C28W	0.997
16:4693815:C:A	A30D	0.997
16:4693987:C:A	R55S	0.997
16:4693993:G:C	D57H	0.997
16:4693994:A:C	D57A	0.997

dbSNP variants (sampled 300 via entrez): RS1000365632 (16:4695990 T>C), RS1000802110 (16:4695812 A>C,G), RS1000987160 (16:4692016 G>A,T), RS1001252440 (16:4691992 C>A), RS1001529054 (16:4696225 G>T), RS1001694522 (16:4692829 G>A,T), RS1001867592 (16:4695399 T>A,C), RS1001898589 (16:4695305 T>A), RS1002125602 (16:4692664 G>A,C,T), RS1002416393 (16:4694861 C>A,G), RS1002439953 (16:4692050 T>C), RS1002723465 (16:4693504 T>C,G), RS1002994485 (16:4693553 G>A,C), RS1003051143 (16:4693667 G>A), RS1003100814 (16:4693605 G>A,T)

Disease associations

OMIM: gene MIM:617338 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724605 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	4
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
deoxynivalenol	decreases expression	1
decabromobiphenyl ether	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
K 7174	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Cadmium	increases expression	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Testosterone	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697661	Binding	Inhibition of NUDT16L1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.