TLK1

Summary

TLK1 (tousled like kinase 1, HGNC:11841) is a protein-coding gene on chromosome 2q31.1, encoding Serine/threonine-protein kinase tousled-like 1 (Q9UKI8). Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S-phase.

The protein encoded by this gene is a serine/threonine kinase that may be involved in the regulation of chromatin assembly. The encoded protein is only active when it is phosphorylated, and this phosphorylation is cell cycle-dependent, with the maximal activity of this protein coming during S phase. The catalytic activity of this protein is diminished by DNA damage and by blockage of DNA replication. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9874 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 82 total
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_012290

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11841
Approved symbol	TLK1
Name	tousled like kinase 1
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0137, PKU-BETA
Ensembl gene	ENSG00000198586
Ensembl biotype	protein_coding
OMIM	608438
Entrez	9874

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000359766, ENST00000360843, ENST00000409443, ENST00000413010, ENST00000431350, ENST00000434911, ENST00000453628, ENST00000466220, ENST00000470340, ENST00000478683, ENST00000486857, ENST00000521943, ENST00000879063, ENST00000928546, ENST00000967137

RefSeq mRNA: 3 — MANE Select: NM_012290 NM_001136554, NM_001136555, NM_012290

CCDS: CCDS2241, CCDS46447, CCDS46448

Canonical transcript exons

ENST00000431350 — 21 exons

Exon	Start	End
ENSE00001778068	170990823	170993956
ENSE00003458475	171082781	171082852
ENSE00003470802	170996653	170996760
ENSE00003502172	171117739	171117857
ENSE00003511374	171046174	171046362
ENSE00003513746	171028339	171028405
ENSE00003522579	171006147	171006282
ENSE00003528496	171055083	171055172
ENSE00003562520	171006972	171007063
ENSE00003564707	171049814	171049950
ENSE00003585055	171058151	171058197
ENSE00003598354	171061081	171061156
ENSE00003618016	171006474	171006643
ENSE00003623412	171014851	171014948
ENSE00003629881	171053761	171053853
ENSE00003637298	171011373	171011454
ENSE00003654280	170997712	170997823
ENSE00003662769	171050064	171050174
ENSE00003669366	171006800	171006889
ENSE00003683614	171056471	171056566
ENSE00003851055	171160290	171160893

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 97.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.6071 / max 426.2672, expressed in 1824 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31766	19.5594	1811
31768	16.3293	1794
31764	2.7027	1236
31767	1.9628	1060
31769	1.4953	780
31765	0.5343	326
31762	0.2778	85
31761	0.2324	67
31763	0.1697	43
202470	0.1526	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.58	gold quality
calcaneal tendon	UBERON:0003701	96.25	gold quality
germinal epithelium of ovary	UBERON:0001304	96.08	gold quality
epithelium of nasopharynx	UBERON:0001951	96.07	gold quality
pigmented layer of retina	UBERON:0001782	95.28	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.28	gold quality
superficial temporal artery	UBERON:0001614	95.25	gold quality
choroid plexus epithelium	UBERON:0003911	95.18	gold quality
substantia nigra pars compacta	UBERON:0001965	94.96	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.90	gold quality
caput epididymis	UBERON:0004358	94.80	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.63	gold quality
Brodmann (1909) area 10	UBERON:0013541	94.58	gold quality
colonic mucosa	UBERON:0000317	94.45	gold quality
corpus epididymis	UBERON:0004359	94.42	gold quality
trabecular bone tissue	UBERON:0002483	94.38	gold quality
seminal vesicle	UBERON:0000998	94.34	gold quality
bone marrow cell	CL:0002092	94.32	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.32	gold quality
colonic epithelium	UBERON:0000397	94.31	gold quality
cauda epididymis	UBERON:0004360	94.23	gold quality
sural nerve	UBERON:0015488	94.21	gold quality
buccal mucosa cell	CL:0002336	94.08	gold quality
palpebral conjunctiva	UBERON:0001812	94.01	gold quality
jejunal mucosa	UBERON:0000399	93.77	gold quality
tibia	UBERON:0000979	93.74	gold quality
tendon	UBERON:0000043	93.57	gold quality
penis	UBERON:0000989	93.54	gold quality
postcentral gyrus	UBERON:0002581	93.49	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.15
E-GEOD-124858	no	2624.41
E-ENAD-27	no	11.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

153 targeting TLK1, 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-4673	100.00	66.64	1490
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 30)

• we show that Chk1 is essential for the suppression of TLK activity after replication block, but that ATR, Chk2 and BRCA1 are dispensable for TLK suppression. (PMID:12955071)
• Both eIF4E and TLK1B are elevated in breast cancer specimens but not in benign breast specimens from noncancer patients. Degree of TLK1B elevation is correlated with degree of IF4E overexpression. (PMID:14732354)
• In addition, it could be demonstrated that increasing the Tlk1 activity in HT1080 cells by forced Tlk1 overexpression leads to an increased phosphorylation of endogenous p68. (PMID:15950181)
• TLK1B promotes the repair of double strand breaks, likely as a consequence of a change in chromatin remodeling capacity that must precede the assembly of repair complexes at the sites of damage (PMID:16156902)
• Studies provide evidence for TLK1B-mediated phosphorylation of Asf1 triggering DNA repair. (PMID:17054786)
• Our data suggest that human PKU-beta/TLK1 plays an important role in chromosome integrity via the regulation of myosin II dynamics by phosphorylating MRLC during mitosis. (PMID:18838128)
• ASF1 cellular levels are tightly controlled by distinct pathways and provide a molecular mechanism for post-translational regulation of dASF1 and hASF1a by TLK kinases. (PMID:20016786)
• Silencing of TLK1 enhanced DNA damage induced by cisplatin treatment, suggesting that TLK1 plays a pivotal role for the repair of cisplatin-induced DNA damage. (PMID:20381954)
• Adenoviral delivery of Tousled kinase protects salivary glands against ionizing radiation damage. (PMID:21048794)
• TLKs appear to be intimately linked to the pattern of resistance to DNA damage, and specifically double-strand breaks. (PMID:21647934)
• Tousled-like kinase-dependent phosphorylation of Rad9 plays a role in cell cycle progression and G2/M checkpoint exit. (PMID:24376897)
• Data indicate Tousled-like kinases (TLK1) phosphorylation has an impact on cell cycle proteins Asf1a and Asf1b function. (PMID:24598821)
• Our results suggest that GA-mediated transient modulation of TLK1 activity promotes DNA repair and suppresses radiation cytoxicity in salivary gland cells. (PMID:26855419)
• TLK1B mediated phosphorylation of Rad9 regulates its nuclear/cytoplasmic localization and cell cycle checkpoint (PMID:26860083)
• Following DNA damage, addition of the TLK1 inhibitor, THD, or overexpression of NEK1-T141A mutant impaired ATR and Chk1 activation, indicating the existence of a TLK1>NEK1>ATR>Chk1 pathway. Indeed, overexpression of the NEK1-T141A mutant resulted in an altered cell cycle response after exposure of cells to oxidative stress, including bypass of G1 arrest and implementation of an intra S-phase checkpoint. (PMID:28426283)
• Overexpression of TLK1 substantially reduces DNA damage and G2/M arrest by activation of TLK1-dependent cell cycle checkpoint response. (PMID:30252587)
• Targeting the TLK1/NEK1 axis might be a novel therapy for PCa. (PMID:30737777)
• Authors believe that this TLK1-Nek1 mediated DDR axis is likely to be a common adaptive response during the transition of PCa cells toward androgen-insensitive growth, and hence CRPC progression. (PMID:30928383)
• The levels of circular RNA TLK1 were significantly increased in the brain tissue and plasma of ischemic stroke patients. (PMID:31311824)
• Variation analysis of tousled like kinase 1 gene in patients with sporadic premature ovarian insufficiency. (PMID:31362519)
• The TLK1/Nek1 axis contributes to mitochondrial integrity and apoptosis prevention via phosphorylation of VDAC1. (PMID:31914854)
• Knockdown of Tousledlike kinase 1 inhibits survival of glioblastoma multiforme cells. (PMID:32468002)
• Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres. (PMID:32755577)
• CircTLK1 modulates sepsis-induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis-mediated mitochondrial DNA damage by sponging miR-17-5p. (PMID:34410682)
• CircTLK1 Downregulation Attenuates High Glucose-Induced Human Mesangial Cell Injury by Blocking the AKT/NF-kappaB Pathway Through Sponging miR-126-5p/miR-204-5p. (PMID:34731387)
• TLK1-mediated MK5-S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies. (PMID:35064619)
• The interaction between ASF1B and TLK1 promotes the malignant progression of low-grade glioma. (PMID:36947060)
• CircTLK1 alleviates oxygen-glucose deprivation/reperfusion induced apoptosis in HK-2 cells through miR-136-5p/Bcl2 signal axis. (PMID:37462140)
• Untousling the Role of Tousled-like Kinase 1 in DNA Damage Repair. (PMID:37686173)
• The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1beta-mediated AML progression. (PMID:38498025)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tlk1a	ENSDARG00000042467
danio_rerio	tlk1b	ENSDARG00000100715
mus_musculus	Tlk1	ENSMUSG00000041997
rattus_norvegicus	Tlk1	ENSRNOG00000009300
drosophila_melanogaster	Tlk	FBGN0283657
caenorhabditis_elegans		WBGENE00006579

Paralogs (2): TTK (ENSG00000112742), TLK2 (ENSG00000146872)

Protein

Protein identifiers

Serine/threonine-protein kinase tousled-like 1 — Q9UKI8 (reviewed: Q9UKI8)

Alternative names: PKU-beta, Tousled-like kinase 1

All UniProt accessions (4): Q9UKI8, B3KRP1, C9JWT6, F8W7X8

UniProt curated annotations — full annotation on UniProt →

Function. Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S-phase. This is cell cycle checkpoint and ATM-pathway dependent and appears to regulate processes involved in chromatin assembly. Isoform 3 phosphorylates and enhances the stability of the t-SNARE SNAP23, augmenting its assembly with syntaxin. Isoform 3 protects the cells from the ionizing radiation by facilitating the repair of DSBs. In vitro, phosphorylates histone H3 at ‘Ser-10’.

Subunit / interactions. Heterodimer with TLK2.

Subcellular location. Nucleus.

Tissue specificity. Widely expressed. Present in fetal placenta, liver, kidney and pancreas but not heart or skeletal muscle. Also found in adult cell lines. Isoform 3 is ubiquitously expressed in all tissues examined.

Activity regulation. Cell-cycle regulated, maximal activity in S-phase. Inactivated by phosphorylation at Ser-743, potentially by CHEK1.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9UKI8-1	1	yes
Q9UKI8-2	2
Q9UKI8-3	3, SNAK, TLK1B
Q9UKI8-4	4
Q9UKI8-5	5

RefSeq proteins (3): NP_001130026, NP_001130027, NP_036422* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (48 total): sequence conflict 11, modified residue 10, compositionally biased region 8, splice variant 5, mutagenesis site 4, binding site 2, region of interest 2, coiled-coil region 2, chain 1, domain 1, active site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKI8-F1	74.43	0.54

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): 586 (proton acceptor)

Ligand- & substrate-binding residues (2): 462–470; 485

Post-translational modifications (10): 38, 54, 77, 80, 134, 159, 174, 176, 743, 1

Mutagenesis-validated functional residues (4):

Position	Phenotype
607	loss of kinase activity.
743	loss of kinase inhibition in response to dna damage.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 219 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, AAGCCAT_MIR135A_MIR135B, MORF_HDAC1, MORF_UBE2N, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GENTILE_RESPONSE_CLUSTER_D3, GGGTGGRR_PAX4_03, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, MORF_SKP1A, DOANE_RESPONSE_TO_ANDROGEN_DN, SASSON_RESPONSE_TO_FORSKOLIN_DN

GO Biological Process (7): chromatin organization (GO:0006325), protein phosphorylation (GO:0006468), intracellular protein transport (GO:0006886), DNA damage response (GO:0006974), chromosome segregation (GO:0007059), intracellular signal transduction (GO:0035556), regulation of chromatin organization (GO:1902275)

GO Molecular Function (8): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	2
cellular component organization	1
phosphorylation	1
protein modification process	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
cellular response to stress	1
cell cycle process	1
intracellular anatomical structure	1
signal transduction	1
chromatin organization	1
regulation of cellular component organization	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1130 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLK1	ASF1B	Q9NVP2	864
TLK1	ASF1A	Q9Y294	842
TLK1	RAD9A	Q99638	829
TLK1	SRSF1	Q07955	815
TLK1	H3-3A	P06351	724
TLK1	H3C1	P02295	724
TLK1	H3C14	Q71DI3	723
TLK1	H3-5	Q6NXT2	723
TLK1	H3-4	Q16695	723
TLK1	H3-7	Q5TEC6	723
TLK1	PRIM1	P49642	552
TLK1	H1-0	P07305	547
TLK1	HELQ	Q8TDG4	538
TLK1	UIMC1	Q96RL1	509
TLK1	MBP	P02686	507
TLK1	POLG	P54098	507

IntAct

101 interactions, top by confidence:

A	B	Type	Score
TLK2	DYNLL1	psi-mi:“MI:0914”(association)	0.890
DYNLL2	TLK1	psi-mi:“MI:0915”(physical association)	0.840
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
TLK1	DYNLL1	psi-mi:“MI:0914”(association)	0.730
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
ASF1A	HAT1	psi-mi:“MI:0914”(association)	0.640
TPM3	TLK1	psi-mi:“MI:0915”(physical association)	0.560
LUZP4	TLK1	psi-mi:“MI:0915”(physical association)	0.560
TLK1	TPM3	psi-mi:“MI:0915”(physical association)	0.560
TLK1	LUZP4	psi-mi:“MI:0915”(physical association)	0.560
TLK1	ZNF773	psi-mi:“MI:0915”(physical association)	0.560
TLK1	ZNF829	psi-mi:“MI:0915”(physical association)	0.560
TLK1	PINX1	psi-mi:“MI:0915”(physical association)	0.560
TLK1	ZNF655	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (234): TLK1 (Two-hybrid), TLK1 (Two-hybrid), LUZP4 (Two-hybrid), TLK1 (Two-hybrid), ASF1A (Two-hybrid), TLK1 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), KIAA1468 (Affinity Capture-MS)

ESM2 similar proteins: A0A8C0TYJ0, A0A8I5ZNK2, A5D7H2, O55047, O88506, O94806, O95747, P00535, P11273, P32298, P34947, P43249, P49137, Q08CW1, Q12959, Q13033, Q15139, Q15700, Q16644, Q1ECX4, Q28C55, Q3SYZ2, Q3UMW7, Q5PYH5, Q5PYH6, Q5R372, Q5R495, Q5RCW6, Q5XIS9, Q62101, Q62696, Q62833, Q63622, Q66H84, Q6P9R2, Q811D0, Q863I2, Q86UE8, Q8BZ03, Q8C0V0

Diamond homologs: A0QNG1, A5D791, A5GFW1, A5TY84, A5U3A3, A5U3A6, A8XJQ6, B0BBT2, O14965, O75716, P0A5S5, P0DPS8, P0DPS9, P18652, P33973, P38070, P41808, P53599, P53739, P54666, P54737, P54744, P57760, P57993, P59241, P9WI70, P9WI71, P9WI74, P9WI75, P9WI76, P9WI77, P9WI78, P9WI79, P9WI80, P9WI81, Q04J43, Q0WPH8, Q255D2, Q2TA06, Q3KM61

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
TLK1	up-regulates	RAD9A	phosphorylation
TLK1	unknown	RAD9A	phosphorylation
TLK1	“up-regulates activity”	MAPKAPK5	phosphorylation
TLK1	“up-regulates activity”	NEK1	phosphorylation
CHEK1	down-regulates	TLK1	phosphorylation
TLK1	“up-regulates activity”	H3C1	phosphorylation
TLK1	“up-regulates activity”	“Histone H3”	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
G2/M Checkpoints	5	15.6×	6e-03
Regulation of PLK1 Activity at G2/M Transition	5	14.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	6	14.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3604 predictions. Top by Δscore:

Variant	Effect	Δscore
2:170993959:C:CT	acceptor_gain	1.0000
2:170993960:A:T	acceptor_gain	1.0000
2:170996762:T:C	acceptor_gain	1.0000
2:171006142:CTTA:C	donor_loss	1.0000
2:171006143:TTACC:T	donor_loss	1.0000
2:171006144:TACCA:T	donor_loss	1.0000
2:171006145:A:AC	donor_gain	1.0000
2:171006145:AC:A	donor_gain	1.0000
2:171006146:C:CA	donor_gain	1.0000
2:171006146:C:G	donor_loss	1.0000
2:171006146:CC:C	donor_gain	1.0000
2:171006146:CCA:C	donor_gain	1.0000
2:171006278:GTTTC:G	acceptor_gain	1.0000
2:171006279:TTTC:T	acceptor_gain	1.0000
2:171006280:TTC:T	acceptor_gain	1.0000
2:171006281:TC:T	acceptor_gain	1.0000
2:171006282:CC:C	acceptor_gain	1.0000
2:171006283:C:CC	acceptor_gain	1.0000
2:171006283:CT:C	acceptor_loss	1.0000
2:171006289:A:C	acceptor_gain	1.0000
2:171006469:ATTAC:A	donor_loss	1.0000
2:171006470:TTACC:T	donor_loss	1.0000
2:171006471:TACCT:T	donor_loss	1.0000
2:171006472:ACC:A	donor_loss	1.0000
2:171006473:C:A	donor_loss	1.0000
2:171006473:CCTGG:C	donor_gain	1.0000
2:171006537:CAAT:C	donor_gain	1.0000
2:171006639:AAAAC:A	acceptor_gain	1.0000
2:171006640:AAAC:A	acceptor_gain	1.0000
2:171006641:AAC:A	acceptor_gain	1.0000

AlphaMissense

5055 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:170993937:A:C	L715W	1.000
2:170993939:A:C	C714W	1.000
2:170993941:A:G	C714R	1.000
2:170996711:A:C	I689R	1.000
2:170996711:A:G	I689T	1.000
2:170996711:A:T	I689K	1.000
2:170996726:A:G	L684P	1.000
2:170996729:A:C	I683S	1.000
2:170996729:A:T	I683N	1.000
2:170996737:T:A	Q680H	1.000
2:170996737:T:G	Q680H	1.000
2:170996753:C:A	G675V	1.000
2:170996753:C:T	G675D	1.000
2:170996754:C:G	G675R	1.000
2:170996755:A:C	F674L	1.000
2:170996755:A:T	F674L	1.000
2:170996756:A:C	F674C	1.000
2:170996756:A:G	F674S	1.000
2:170996757:A:G	F674L	1.000
2:170996757:A:T	F674I	1.000
2:170996759:G:C	P673R	1.000
2:170996759:G:T	P673Q	1.000
2:170996760:G:A	P673S	1.000
2:170997712:C:A	K672N	1.000
2:170997712:C:G	K672N	1.000
2:170997714:T:C	K672E	1.000
2:170997746:C:A	G661V	1.000
2:170997746:C:T	G661E	1.000
2:170997747:C:G	G661R	1.000
2:170997747:C:T	G661R	1.000

dbSNP variants (sampled 300 via entrez): RS1000003956 (2:171044438 ATTTGT>A), RS1000008201 (2:171003045 CG>C,CGGG), RS1000009064 (2:171040613 C>T), RS1000041822 (2:171084032 G>A), RS1000061691 (2:171171892 C>A,T), RS1000081113 (2:171215152 G>A,T), RS1000086299 (2:171139731 C>G), RS1000107477 (2:171211276 C>G,T), RS1000119884 (2:171040437 T>C), RS1000122834 (2:171193912 G>T), RS1000164399 (2:171028235 T>C), RS1000165609 (2:171197041 G>A,T), RS1000186666 (2:171108827 C>T), RS1000204410 (2:171063355 A>G), RS1000204652 (2:171016670 T>C,G)

Disease associations

OMIM: gene MIM:608438 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001381_12	Menopause (age at onset)	2.000000e-14
GCST004616_131	Platelet distribution width	7.000000e-10
GCST005312_34	Menopause (age at onset)	3.000000e-19
GCST008513_4	Health literacy	8.000000e-06
GCST012466_1	Autism spectrum disorder	4.000000e-06
GCST90002401_389	Platelet distribution width	5.000000e-19
GCST90013406_161	Liver enzyme levels (alkaline phosphatase)	4.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0007984	platelet component distribution width
EFO:0010104	health literacy measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5388 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 105,474 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL535	SUNITINIB	4	79,020
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1721885	SU-014813	2	363
CHEMBL445813	AT-7519	2	2,614
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL1908397	KW-2449	1	622

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Tousled-like kinase (TLK) family

Binding affinities (BindingDB)

3 measured of 3 human assays (3 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

30 potent at pChembl≥5 of 31 total, top 22 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.66	IC50	21.7	nM	STAUROSPORINE
7.57	Kd	27	nM	STAUROSPORINE
7.52	IC50	30.4	nM	STAUROSPORINE
7.44	IC50	36.4	nM	STAUROSPORINE
7.29	IC50	51.2	nM	STAUROSPORINE
6.96	Kd	110	nM	LESTAURTINIB
6.31	Kd	490	nM	R-406
6.29	Kd	510	nM	ENZASTAURIN
6.24	Kd	570	nM	BOSUTINIB
6.20	Kd	630	nM	CHEMBL5527885
6.20	Kd	630	nM	SU-014813
6.13	Kd	740	nM	SUNITINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.96	Kd	1100	nM	JNJ-7706621
5.92	IC50	1200	nM	CHEMBL5205578
5.89	Kd	1300	nM	FEDRATINIB
5.68	Kd	2100	nM	RUBOXISTAURIN
5.62	Kd	2400	nM	AT-7519
5.57	Kd	2700	nM	KW-2449
5.40	Kd	4000	nM	TOZASERTIB

PubChem BioAssay actives

28 with measured affinity, of 320 total; 16 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1531908: Inhibition of human TLK1 using Histone H3 as substrate by [gamma-33P]-ATP assay	ic50	0.0217	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	508111: Binding affinity to TLK1	kd	0.1100	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	2062924: Inhibition of TLK1 (unknown origin)	kd	0.4900	uM
3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione	625069: Binding constant for TLK1 kinase domain	kd	0.5100	uM
Bosutinib	625069: Binding constant for TLK1 kinase domain	kd	0.5700	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435199: Binding constant for TLK1 kinase domain	kd	0.6300	uM
5-[(E)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	2062924: Inhibition of TLK1 (unknown origin)	kd	0.6300	uM
Sunitinib	2062924: Inhibition of TLK1 (unknown origin)	kd	0.7400	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435199: Binding constant for TLK1 kinase domain	kd	1.1000	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-chloro-2-pyridinyl]-2-pyridinyl]carbamate	1904678: Inhibition of TLK1 (unknown origin)	ic50	1.2000	uM
Fedratinib	625069: Binding constant for TLK1 kinase domain	kd	1.3000	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	625069: Binding constant for TLK1 kinase domain	kd	2.1000	uM
4-[(2,6-dichlorobenzoyl)amino]-N-piperidin-4-yl-1H-pyrazole-5-carboxamide	625069: Binding constant for TLK1 kinase domain	kd	2.4000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625069: Binding constant for TLK1 kinase domain	kd	2.7000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	625069: Binding constant for TLK1 kinase domain	kd	4.0000	uM
3-[(3S)-3-aminopyrrolidine-1-carbonyl]-5,10-dihydroxy-2-methylnaphtho[2,3-f][1]benzofuran-4,11-dione;methanesulfonic acid	1284065: Inhibition of human N-terminal FLAG, C-terminal HIS8-tagged TLK1 expressed in sf9 cells by flashplate based radiometric 33pan-quinase assay	ic50	5.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	8
trichostatin A	affects cotreatment, decreases expression, affects expression	4
Acetaminophen	decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
geldanamycin	increases expression	1
lasiocarpine	increases metabolic processing, decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
bisphenol A	increases expression	1
riddelliine	decreases expression, increases metabolic processing	1
arsenite	affects binding, decreases reaction	1
4-chloro-1,2-diaminobenzene	affects response to substance	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Fulvestrant	increases methylation	1
Vorinostat	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	affects phosphorylation	1
Doxorubicin	affects expression	1
Formaldehyde	decreases expression	1
Gold	increases expression	1
Lipopolysaccharides	increases expression	1

ChEMBL screening assays

191 unique, capped per target: 191 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1059379	Binding	Inhibition of TLK1 assessed as enzyme activity at 1 uM relative to untreated control	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — J Med Chem

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A7M9	SEES3-1V human TLK1, clone1	Embryonic stem cell	Male
CVCL_A7N0	SEES3-1V human TLK1, clone2	Embryonic stem cell	Male
CVCL_A7N1	SEES3-1V human TLK1, clone3	Embryonic stem cell	Male
CVCL_B2IN	Abcam HeLa TLK1 KO	Cancer cell line	Female
CVCL_TS52	HAP1 TLK1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice