TSPYL5

Summary

TSPYL5 (TSPY like 5, HGNC:29367) is a protein-coding gene on chromosome 8q22.1, encoding Testis-specific Y-encoded-like protein 5 (Q86VY4). Involved in modulation of cell growth and cellular response to gamma radiation probably via regulation of the Akt signaling pathway. It is a selective cancer dependency (DepMap: 40.9% of cell lines).

Predicted to enable chromatin binding activity and histone binding activity. Involved in several processes, including cellular response to gamma radiation; positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; and positive regulation of protein ubiquitination. Predicted to be active in chromatin and nucleus.

Source: NCBI Gene 85453 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Cancer dependency (DepMap): dependent in 40.9% of screened cell lines
• MANE Select transcript: NM_033512

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29367
Approved symbol	TSPYL5
Name	TSPY like 5
Location	8q22.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1750
Ensembl gene	ENSG00000180543
Ensembl biotype	protein_coding
OMIM	614721
Entrez	85453

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000322128

RefSeq mRNA: 1 — MANE Select: NM_033512 NM_033512

CCDS: CCDS34927

Canonical transcript exons

ENST00000322128 — 1 exons

Exon	Start	End
ENSE00001243223	97273488	97277928

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 96.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.1982 / max 220.5806, expressed in 1268 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94069	10.1982	1268

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.40	gold quality
adult organism	UBERON:0007023	95.92	gold quality
seminal vesicle	UBERON:0000998	95.19	gold quality
dorsal root ganglion	UBERON:0000044	93.30	gold quality
corpus epididymis	UBERON:0004359	93.19	gold quality
cauda epididymis	UBERON:0004360	92.71	gold quality
superior vestibular nucleus	UBERON:0007227	92.68	gold quality
testis	UBERON:0000473	92.63	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.49	gold quality
mammary duct	UBERON:0001765	92.30	gold quality
trigeminal ganglion	UBERON:0001675	91.97	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.95	gold quality
epithelium of mammary gland	UBERON:0003244	91.93	gold quality
pons	UBERON:0000988	91.91	gold quality
right testis	UBERON:0004534	91.71	gold quality
caput epididymis	UBERON:0004358	91.70	gold quality
oocyte	CL:0000023	91.65	gold quality
lateral globus pallidus	UBERON:0002476	91.63	gold quality
left ventricle myocardium	UBERON:0006566	91.54	gold quality
left testis	UBERON:0004533	91.50	gold quality
orbitofrontal cortex	UBERON:0004167	91.44	gold quality
substantia nigra pars compacta	UBERON:0001965	91.35	gold quality
cartilage tissue	UBERON:0002418	91.30	gold quality
urethra	UBERON:0000057	91.16	gold quality
myocardium	UBERON:0002349	91.01	gold quality
Brodmann (1909) area 10	UBERON:0013541	90.99	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.77	gold quality
postcentral gyrus	UBERON:0002581	90.66	gold quality
male germ cell	CL:0000015	90.50	gold quality
diaphragm	UBERON:0001103	90.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

146 targeting TSPYL5, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-8087	99.90	69.55	1351

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 40.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• aberrant methylation at a CpG island of TSPYL5 may play an important role in development of gastric cancers (PMID:18059362)
• This study provides the first demonstration that TSPYL5 modulates cell growth and sensitization of cells to the detrimental effects of damaging agents via regulation of p21(WAF1/Cip1) and PTEN/AKT pathway. (PMID:20079711)
• Data identify TSPYL5 as a suppressor of p53 function through its interaction with USP7. (PMID:21170034)
• TSPYL5 knockdown decreased, and overexpression increased aromatase (CYP19A1) expression through the skin/adipose (I.4) promoter. (PMID:23518928)
• Suggest that hypermethylation of ACP1, BMP4, and TSPYL5 are common events in HCC and could be used as potentially detectable biomarkers in HCC tissues. (PMID:26386860)
• TSPYL5 overexpression is associated with Down syndrome. (PMID:26911678)
• Transcriptome analysis of MUC16 KD showed a downregulation (P = 0.005) of TSPYL5 gene, which encodes for a testis-specific Y-like protein…Also, MUC16 overexpression induced cisplatin and gemcitabine resistance by downregulation of p53 (PMID:28196872)
• More advanced tumor tissues had an inverse correlation between methylation and TSPYL5 gene or protein expression. TSPYL5 may play a role in sensitivity to chemotherapy likely by modulating pleiotropic protein such as CDKN1A. (PMID:28235398)
• The expression of spermatogenic phenotypes of TSPY1 defects is independent of variations in TSPYL1 and TSPYL5 in the Han Chinese population. (PMID:28847364)
• Overexpression of miR-629 promoted the cell ability of migration and invasion and reduced ovarian cancer cell apoptosis. In addition, elevated cancer inhibition ability of TSPYL5 induced by the miR-629 inhibitor was significantly blocked by inhibition of TSPYL5. (PMID:28972400)
• Increasing the expression of TSPYL5 in HT29 cells or inhibiting miR-19-5p promotes apoptosis of HT29 cells. (PMID:29240449)
• TSPYL5, a novel angiogenic regulator, plays a key role in maintaining endothelial integrity and function. (PMID:30471052)
• PML depletion suppressed POT1 poly-ubiquitination, suggesting an interplay between USP7 and PML to trigger POT1 degradation in TSPYL5-depleted ALT(+) cells. We demonstrate that ALT telomeres need to be protected from POT1 degradation in ALT-associated PML bodies and identify TSPYL5 as an ALT(+) cancer-specific therapeutic target. (PMID:31278054)
• TSPYL5 activates endoplasmic reticulum stress to inhibit cell proliferation, migration and invasion in colorectal cancer. (PMID:32627024)
• Human testis-specific Y-encoded protein-like protein 5 is a histone H3/H4-specific chaperone that facilitates histone deposition in vitro. (PMID:35772497)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	tspy	ENSDARG00000005015
danio_rerio	nap1l4a	ENSDARG00000070560
mus_musculus	Tspyl5	ENSMUSG00000038984
rattus_norvegicus	Tspyl5	ENSRNOG00000006278
drosophila_melanogaster	Set	FBGN0014879
drosophila_melanogaster	Nap1	FBGN0015268
drosophila_melanogaster	CG3708	FBGN0040345
drosophila_melanogaster	mil	FBGN0267366
caenorhabditis_elegans		WBGENE00005007
caenorhabditis_elegans		WBGENE00017075

Paralogs (19): SET (ENSG00000119335), TSPY2 (ENSG00000168757), NAP1L5 (ENSG00000177432), TSPYL6 (ENSG00000178021), TSPYL2 (ENSG00000184205), NAP1L3 (ENSG00000186310), NAP1L2 (ENSG00000186462), NAP1L1 (ENSG00000187109), TSPYL4 (ENSG00000187189), TSPYL1 (ENSG00000189241), NAP1L4 (ENSG00000205531), TSPY3 (ENSG00000228927), TSPY8 (ENSG00000229549), SETSIP (ENSG00000230667), TSPY4 (ENSG00000233803), TSPY10 (ENSG00000236424), TSPY9 (ENSG00000238074), TSPY1 (ENSG00000258992), (ENSG00000293164)

Protein

Protein identifiers

Testis-specific Y-encoded-like protein 5 — Q86VY4 (reviewed: Q86VY4)

All UniProt accessions (1): Q86VY4

UniProt curated annotations — full annotation on UniProt →

Function. Involved in modulation of cell growth and cellular response to gamma radiation probably via regulation of the Akt signaling pathway. Involved in regulation of p53/TP53. Suppresses p53/TP53 protein levels and promotes its ubiquitination; the function is dependent on USP7 and independent on MDM2. Proposed to displace p53/TP53 from interaction with USP7.

Subunit / interactions. Interacts with USP7.

Similarity. Belongs to the nucleosome assembly protein (NAP) family.

RefSeq proteins (1): NP_277047* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002164	NAP	Family
IPR037231	NAP-like_sf	Homologous_superfamily

Pfam: PF00956

UniProt features (12 total): compositionally biased region 5, region of interest 4, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86VY4-F1	63.98	0.32

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 150 (showing top): GOBP_RESPONSE_TO_IONIZING_RADIATION, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_CELLULAR_RESPONSE_TO_GAMMA_RADIATION, BROWNE_HCMV_INFECTION_24HR_UP, ONKEN_UVEAL_MELANOMA_UP, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, ATF1_Q6, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, CAIRO_HEPATOBLASTOMA_DN, E4F1_Q6, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOBP_RESPONSE_TO_RADIATION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, NIKOLSKY_BREAST_CANCER_8Q12_Q22_AMPLICON, GOBP_CELLULAR_RESPONSE_TO_IONIZING_RADIATION

GO Biological Process (6): nucleosome assembly (GO:0006334), positive regulation of cell population proliferation (GO:0008284), positive regulation of protein ubiquitination (GO:0031398), protein homooligomerization (GO:0051260), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular response to gamma radiation (GO:0071480)

GO Molecular Function (3): chromatin binding (GO:0003682), histone binding (GO:0042393), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
protein complex oligomerization	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
response to gamma radiation	1
cellular response to ionizing radiation	1
protein binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

830 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSPYL5	USP7	Q93009	867
TSPYL5	CCNE2	O96020	450
TSPYL5	ZKSCAN2	Q63HK3	434
TSPYL5	MINDY4	Q4G0A6	433
TSPYL5	SPOCD1	Q6ZMY3	432
TSPYL5	DNAJC9	Q8WXX5	424
TSPYL5	DCK	P27707	418
TSPYL5	LYG1	Q8N1E2	402
TSPYL5	ZNF507	Q8TCN5	402
TSPYL5	ZNF610	Q8N9Z0	399
TSPYL5	B3GALT6	Q96L58	398
TSPYL5	CD55	P08174	396
TSPYL5	BBC3	Q96PG8	387
TSPYL5	SLC16A5	O15375	381
TSPYL5	MUC1	P13931	380

IntAct

14 interactions, top by confidence:

A	B	Type	Score
USP7	TSPYL5	psi-mi:“MI:0915”(physical association)	0.590
TSPYL5	USP7	psi-mi:“MI:0915”(physical association)	0.590
TSPYL5	ISG15	psi-mi:“MI:0915”(physical association)	0.400
C9orf72	CHD2	psi-mi:“MI:0914”(association)	0.350
TSPYL5	CBX4	psi-mi:“MI:0914”(association)	0.350
TSPYL5	MACROH2A1	psi-mi:“MI:0914”(association)	0.350
FASTKD2	MED19	psi-mi:“MI:2364”(proximity)	0.270
LIN28B	MEX3A	psi-mi:“MI:2364”(proximity)	0.270
RPS3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
SMNDC1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
SUPV3L1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (63): TSPYL5 (Affinity Capture-MS), TSPYL5 (Two-hybrid), TSPY1 (Affinity Capture-Western), TSPYL5 (Affinity Capture-Western), TSPY1 (Co-localization), USP7 (Affinity Capture-Western), TSPYL5 (Positive Genetic), TSPYL5 (Affinity Capture-MS), TSPYL5 (Proximity Label-MS), RPL23A (Affinity Capture-MS), DAXX (Affinity Capture-MS), TSPYL5 (Affinity Capture-MS), TSPYL5 (Affinity Capture-MS), TSPYL5 (Affinity Capture-MS), NONO (Affinity Capture-MS)

ESM2 similar proteins: A0A494C1R9, A2AKB4, A2APT9, A6NKD2, A8MT33, B0BN44, E9PGG2, F5GYI3, O19110, O88852, P0CV98, P0CV99, P0CW00, P0CW01, Q01534, Q03386, Q0P5N2, Q12967, Q14684, Q2M329, Q3U3N0, Q5F267, Q5I0E2, Q5R5G8, Q5R866, Q5SYB0, Q5VTJ3, Q60953, Q69ZB3, Q6ZUX3, Q7TQI8, Q80VJ8, Q80VR2, Q86VY4, Q8BSI6, Q8IZJ4, Q8N831, Q8VD63, Q95LS7, Q96FG2

Diamond homologs: A0A494C1R9, A2ZX50, A6NKD2, B8AEC1, B8B2R4, B8B4K9, B9FU45, F4JEI8, O19110, O59797, O88852, P0CV98, P0CV99, P0CW00, P0CW01, P0DME0, P53997, P78920, Q01105, Q01534, Q0P5N2, Q18240, Q5R5G8, Q5VND6, Q63945, Q69JW2, Q69ZB3, Q70Z17, Q70Z18, Q70Z19, Q7TQI8, Q86VY4, Q8N831, Q8VD63, Q94K07, Q9BE64, Q9CA59, Q9EQU5, Q9H0U9, Q9H2G4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

230 predictions. Top by Δscore:

Variant	Effect	Δscore
8:97277718:TCTGG:T	donor_gain	0.9700
8:97277820:TTCG:T	donor_gain	0.9700
8:97277709:C:A	donor_gain	0.9600
8:97277724:A:AC	donor_gain	0.9500
8:97277725:C:CC	donor_gain	0.9500
8:97277719:CTGGT:C	donor_gain	0.9400
8:97277708:T:TA	donor_gain	0.9300
8:97277160:T:TA	donor_gain	0.9200
8:97277406:T:TA	donor_gain	0.8900
8:97277407:C:A	donor_gain	0.8900
8:97275907:C:T	acceptor_gain	0.8800
8:97276881:C:CT	donor_gain	0.8700
8:97277720:TGG:T	donor_gain	0.8700
8:97275907:C:CT	acceptor_gain	0.8600
8:97276882:C:CT	donor_gain	0.8600
8:97277456:C:A	donor_gain	0.8400
8:97277455:T:TA	donor_gain	0.8100
8:97277121:T:TA	donor_gain	0.7900
8:97277696:G:GA	donor_gain	0.7800
8:97277717:CTCTG:C	donor_gain	0.7800
8:97277384:C:CT	donor_gain	0.7600
8:97277385:T:TT	donor_gain	0.7600
8:97277085:G:A	donor_gain	0.7400
8:97277833:T:TA	donor_gain	0.7200
8:97276880:A:AC	donor_gain	0.6400
8:97275894:CAG:C	acceptor_gain	0.6000
8:97276910:T:TA	donor_gain	0.6000
8:97276919:A:AC	donor_gain	0.5900
8:97274360:ACACC:A	acceptor_loss	0.5800
8:97274362:ACCTA:A	acceptor_loss	0.5800

AlphaMissense

2702 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:97276857:A:G	W330R	0.999
8:97276857:A:T	W330R	0.999
8:97276912:C:A	K311N	0.999
8:97276912:C:G	K311N	0.999
8:97277092:G:C	F251L	0.999
8:97277092:G:T	F251L	0.999
8:97277094:A:G	F251L	0.999
8:97276725:A:G	W374R	0.998
8:97276725:A:T	W374R	0.998
8:97276727:A:G	L373S	0.998
8:97276739:A:T	I369N	0.998
8:97276788:A:G	W353R	0.998
8:97276788:A:T	W353R	0.998
8:97276934:A:G	F304S	0.998
8:97276951:G:C	F298L	0.998
8:97276951:G:T	F298L	0.998
8:97276953:A:G	F298L	0.998
8:97276958:A:G	F296S	0.998
8:97277089:C:A	W252C	0.998
8:97277089:C:G	W252C	0.998
8:97277091:A:G	W252R	0.998
8:97277091:A:T	W252R	0.998
8:97277122:C:A	R241S	0.998
8:97277122:C:G	R241S	0.998
8:97277155:A:C	F230L	0.998
8:97277155:A:T	F230L	0.998
8:97277157:A:G	F230L	0.998
8:97276723:C:A	W374C	0.997
8:97276723:C:G	W374C	0.997
8:97276739:A:C	I369S	0.997

dbSNP variants (sampled 300 via entrez): RS1000173029 (8:97278008 G>A,T), RS1000266731 (8:97274041 C>T), RS1000630836 (8:97276048 G>A), RS1001083611 (8:97274808 GGCCCAGCTCT>G), RS1001544059 (8:97274864 T>C), RS1001634586 (8:97279922 T>G), RS1001771837 (8:97279599 C>T), RS1001911314 (8:97274630 T>G), RS1002112569 (8:97273992 C>A,G), RS1002640544 (8:97278439 T>C), RS1002766724 (8:97278192 A>G), RS1002854965 (8:97273029 C>A,G), RS1002962301 (8:97275991 G>A,C), RS1003327047 (8:97274240 C>A,T), RS1004324055 (8:97277939 C>A,T)

Disease associations

OMIM: gene MIM:614721 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001914_17	Estradiol plasma levels (breast cancer)	3.000000e-08
GCST003629_14	Nicotine metabolite ratio in current smokers	3.000000e-08
GCST007277_11	Tourette syndrome	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004697	estradiol measurement
EFO:0007794	nicotine metabolite ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, increases expression	5
Arsenic	decreases expression, increases abundance, decreases response to substance	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
trichostatin A	increases expression	1
afimoxifene	decreases reaction, increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
avobenzone	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Estrogens	decreases reaction, increases expression	1
Ribonucleotides	affects binding	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	increases expression	1
Genistein	affects binding, increases reaction	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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