ORC5

Summary

ORC5 (origin recognition complex subunit 5, HGNC:8491) is a protein-coding gene on chromosome 7q22.1-q22.2, encoding Origin recognition complex subunit 5 (O43913). Component of the origin recognition complex (ORC) that binds origins of replication. It is a selective cancer dependency (DepMap: 42.6% of cell lines).

The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. The protein encoded by this gene is a subunit of the ORC complex. Alternatively spliced transcript variants encoding distinct isoforms have been described.

Source: NCBI Gene 5001 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 76 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 42.6% of screened cell lines
• MANE Select transcript: NM_002553

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8491
Approved symbol	ORC5
Name	origin recognition complex subunit 5
Location	7q22.1-q22.2
Locus type	gene with protein product
Status	Approved
Aliases	Orc5p, ORC5T, PPP1R117
Ensembl gene	ENSG00000164815
Ensembl biotype	protein_coding
OMIM	602331
Entrez	5001

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000297431, ENST00000422497, ENST00000447452, ENST00000448563, ENST00000463152, ENST00000477223, ENST00000485726, ENST00000626700, ENST00000884266, ENST00000884267, ENST00000884268, ENST00000938616, ENST00000938617, ENST00000938618, ENST00000938619, ENST00000938620, ENST00000953176, ENST00000953177, ENST00000953178, ENST00000953179

RefSeq mRNA: 2 — MANE Select: NM_002553 NM_002553, NM_181747

CCDS: CCDS47681, CCDS5734

Canonical transcript exons

ENST00000297431 — 14 exons

Exon	Start	End
ENSE00001720574	104126341	104126893
ENSE00003477530	104161072	104161182
ENSE00003479145	104166772	104166884
ENSE00003491443	104184123	104184171
ENSE00003508749	104204142	104204234
ENSE00003508846	104136781	104136893
ENSE00003561371	104200758	104200958
ENSE00003565609	104165235	104165282
ENSE00003572322	104188251	104188381
ENSE00003608394	104197725	104197799
ENSE00003621756	104183943	104184033
ENSE00003638531	104195143	104195254
ENSE00003679157	104168473	104168525
ENSE00003848382	104207833	104208013

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5291 / max 83.3276, expressed in 1751 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85392	11.5291	1751

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.03	gold quality
oocyte	CL:0000023	97.59	gold quality
endothelial cell	CL:0000115	93.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.93	gold quality
middle temporal gyrus	UBERON:0002771	89.16	gold quality
buccal mucosa cell	CL:0002336	88.99	silver quality
Brodmann (1909) area 23	UBERON:0013554	88.84	gold quality
ventricular zone	UBERON:0003053	87.00	gold quality
calcaneal tendon	UBERON:0003701	86.17	gold quality
adrenal tissue	UBERON:0018303	85.89	gold quality
body of pancreas	UBERON:0001150	85.52	gold quality
esophagus squamous epithelium	UBERON:0006920	85.41	gold quality
rectum	UBERON:0001052	85.40	gold quality
prefrontal cortex	UBERON:0000451	84.61	gold quality
ganglionic eminence	UBERON:0004023	84.43	gold quality
mucosa of transverse colon	UBERON:0004991	84.21	gold quality
testis	UBERON:0000473	84.10	gold quality
pancreas	UBERON:0001264	84.10	gold quality
cortical plate	UBERON:0005343	84.06	gold quality
sperm	CL:0000019	83.85	gold quality
primary visual cortex	UBERON:0002436	83.78	gold quality
tibial nerve	UBERON:0001323	83.76	gold quality
gingival epithelium	UBERON:0001949	83.74	gold quality
right testis	UBERON:0004534	83.73	gold quality
cerebellar hemisphere	UBERON:0002245	83.72	gold quality
cerebellar cortex	UBERON:0002129	83.70	gold quality
right adrenal gland	UBERON:0001233	83.59	gold quality
right adrenal gland cortex	UBERON:0035827	83.53	gold quality
skin of leg	UBERON:0001511	83.49	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	202.91
E-ANND-3	yes	5.23
E-MTAB-7606	no	417.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting ORC5, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-508-5P	99.41	64.25	1248

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 42.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• Orc5 associates with the H3 histone acetyl transferase GCN5 (also known as KAT2A), and this association enhances the chromatin-opening function of Orc5. (PMID:26644179)
• A human cancer cell line initiates DNA replication normally in the absence of ORC5 and ORC2 proteins. (PMID:32989049)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	orc5	ENSDARG00000021579
mus_musculus	Orc5	ENSMUSG00000029012
rattus_norvegicus	Orc5	ENSRNOG00000011519
drosophila_melanogaster	Orc5	FBGN0015271
caenorhabditis_elegans		WBGENE00013857

Protein

Protein identifiers

Origin recognition complex subunit 5 — O43913 (reviewed: O43913)

All UniProt accessions (3): A4D0P7, O43913, G3V0H0

UniProt curated annotations — full annotation on UniProt →

Function. Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.

Subunit / interactions. Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Abundant in spleen, ovary, prostate, testis, and colon mucosa.

Post-translational modifications. Multi-mono-ubiquitinated by OBI1; ubiquitination is important for efficient DNA replication origin site activation. Ubiquitination levels are low in mitotic and early G1-phAse cells and are induced in late G1-/early S-phase, peaking in S-phase and decrease toward the end of the cell cycle.

Miscellaneous. Does not interact with ORC2.

Similarity. Belongs to the ORC5 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43913-1	1	yes
O43913-2	2, ORC5T

RefSeq proteins (2): NP_002544, NP_859531 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR020796	ORC5	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041664	AAA_16	Domain
IPR047088	ORC5_C	Domain
IPR048866	ORC5_lid	Domain

Pfam: PF13191, PF14630, PF21639

Enzyme classification (BRENDA):

• EC 3.6.4.B8 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (47 total): helix 21, strand 14, turn 6, sequence variant 3, chain 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
7JPO	ELECTRON MICROSCOPY	3.2
5UJ7	X-RAY DIFFRACTION	3.39
7JPQ	ELECTRON MICROSCOPY	3.5
8S0D	ELECTRON MICROSCOPY	3.6
7JPP	ELECTRON MICROSCOPY	3.7
7CTE	ELECTRON MICROSCOPY	3.8
8S0E	ELECTRON MICROSCOPY	3.8
7JPR	ELECTRON MICROSCOPY	4
8S0C	ELECTRON MICROSCOPY	4
8S0F	ELECTRON MICROSCOPY	4.1
7JPS	ELECTRON MICROSCOPY	4.4
7CTF	ELECTRON MICROSCOPY	4.8
7CTG	ELECTRON MICROSCOPY	5
8RWV	ELECTRON MICROSCOPY	6.68
5UJM	ELECTRON MICROSCOPY	18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43913-F1	82.43	0.36

Functional residue map

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

Ligand- & substrate-binding residues (1): 37–44

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-113507	E2F-enabled inhibition of pre-replication complex formation
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-68616	Assembly of the ORC complex at the origin of replication
R-HSA-68689	CDC6 association with the ORC:origin complex
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-68949	Orc1 removal from chromatin
R-HSA-68962	Activation of the pre-replicative complex

MSigDB gene sets: 0 (showing top):

GO Biological Process (3): DNA replication (GO:0006260), DNA replication initiation (GO:0006270), regulation of DNA replication (GO:0006275)

GO Molecular Function (4): nucleotide binding (GO:0000166), DNA replication origin binding (GO:0003688), ATP binding (GO:0005524), protein binding (GO:0005515)

GO Cellular Component (8): chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), origin recognition complex (GO:0000808), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear origin of replication recognition complex (GO:0005664), cytosol (GO:0005829), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Assembly of the pre-replicative complex	2
DNA Replication Pre-Initiation	2
E2F mediated regulation of DNA replication	1
G2/M Checkpoints	1
Switching of origins to a post-replicative state	1
G1/S Transition	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA metabolic process	2
chromosome	2
DNA biosynthetic process	1
DNA-templated DNA replication	1
DNA replication	1
regulation of DNA metabolic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
sequence-specific double-stranded DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
binding	1
chromosomal region	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear chromosome	1
origin recognition complex	1
nuclear protein-containing complex	1
cytoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2022 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORC5	ORC4	O43929	999
ORC5	ORC6	Q9Y5N6	998
ORC5	ORC3	Q9UBD5	997
ORC5	ORC1	Q13415	968
ORC5	ORC2	Q13416	937
ORC5	MCM4	P33991	833
ORC5	MCM5	P33992	829
ORC5	MCM7	P33993	824
ORC5	MCM3	P25205	823
ORC5	MCM6	Q14566	815
ORC5	CDC6	Q99741	796
ORC5	CDT1	Q9H211	773
ORC5	CDC7	O00311	752
ORC5	KAT2A	Q92830	751
ORC5	CDC45	O75419	717

IntAct

121 interactions, top by confidence:

A	B	Type	Score
ORC1	ORC5	psi-mi:“MI:0915”(physical association)	0.870
ORC1	ORC5	psi-mi:“MI:0914”(association)	0.870
ORC1	ORC5	psi-mi:“MI:0407”(direct interaction)	0.870
ORC5	ORC1	psi-mi:“MI:0915”(physical association)	0.870
ORC2	ORC5	psi-mi:“MI:0914”(association)	0.810
ORC2	ORC5	psi-mi:“MI:0915”(physical association)	0.810
ORC2	ORC5	psi-mi:“MI:0407”(direct interaction)	0.810
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620

BioGRID (157): NIF3L1 (Two-hybrid), ORC5 (Protein-peptide), ORC5 (Protein-peptide), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), ORC5 (Affinity Capture-MS)

ESM2 similar proteins: A0A8J1LLF7, A0A974H8H3, A0MQH0, A4FUD6, B3DLA6, E1C1R4, O43913, P11029, P11497, P42694, P54198, Q13085, Q25BN1, Q28559, Q4R4U1, Q504Q3, Q5F450, Q5R5F8, Q5R660, Q5R8I6, Q5RCC1, Q5SWU9, Q5ZIT8, Q61666, Q6DFV5, Q6IE70, Q6NYU2, Q6P1X5, Q6TUI4, Q6TV19, Q8BGF7, Q8BHL5, Q8BPU7, Q8C176, Q8CIQ7, Q8IZD9, Q8K0F1, Q8R418, Q8R5L3, Q8VHE0

Diamond homologs: O43913, Q24169, Q9WUV0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ORC5	“form complex”	ORC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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
Activation of the pre-replicative complex	11	66.5×	1e-15
Activation of ATR in response to replication stress	11	61.2×	2e-15
DNA Replication Pre-Initiation	6	35.2×	6e-07
Orc1 removal from chromatin	9	29.7×	1e-09
Synthesis of DNA	5	27.8×	2e-05
DNA Replication	6	26.4×	3e-06
G1/S Transition	6	25.9×	3e-06
Mitotic G1 phase and G1/S transition	7	23.9×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
DNA replication initiation	11	90.3×	6e-17

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2237 predictions. Top by Δscore:

Variant	Effect	Δscore
7:104168380:T:TA	donor_gain	1.0000
7:104168406:A:C	donor_gain	1.0000
7:104168415:T:C	donor_gain	1.0000
7:104168427:G:C	donor_gain	1.0000
7:104168462:T:TA	donor_gain	1.0000
7:104168463:C:A	donor_gain	1.0000
7:104168526:C:CC	acceptor_gain	1.0000
7:104184040:C:CT	acceptor_gain	1.0000
7:104184041:A:T	acceptor_gain	1.0000
7:104188246:TTTAC:T	donor_loss	1.0000
7:104188247:TTA:T	donor_loss	1.0000
7:104188248:TACCA:T	donor_loss	1.0000
7:104188249:A:AG	donor_loss	1.0000
7:104188250:C:A	donor_loss	1.0000
7:104197719:ACTT:A	donor_loss	1.0000
7:104197720:CTT:C	donor_loss	1.0000
7:104197722:TACCA:T	donor_loss	1.0000
7:104197723:A:AC	donor_gain	1.0000
7:104197723:ACC:A	donor_loss	1.0000
7:104197724:C:CC	donor_gain	1.0000
7:104197724:C:T	donor_loss	1.0000
7:104197724:CCAA:C	donor_gain	1.0000
7:104197799:CCTT:C	acceptor_gain	1.0000
7:104197802:T:TC	acceptor_gain	1.0000
7:104200753:CT:C	donor_loss	1.0000
7:104200754:TTAC:T	donor_loss	1.0000
7:104200755:T:TG	donor_loss	1.0000
7:104200756:A:AC	donor_gain	1.0000
7:104200756:A:AT	donor_loss	1.0000
7:104200757:C:A	donor_loss	1.0000

AlphaMissense

2866 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:104188261:A:G	L225P	0.999
7:104195222:A:C	S158R	0.999
7:104195222:A:T	S158R	0.999
7:104195224:T:G	S158R	0.999
7:104136883:A:G	L387P	0.998
7:104166818:A:G	L315P	0.998
7:104136816:G:C	C409W	0.997
7:104136818:A:G	C409R	0.997
7:104166822:A:C	Y314D	0.997
7:104166827:G:T	A312D	0.997
7:104183985:A:G	L261S	0.997
7:104188252:A:G	L228P	0.997
7:104204197:C:T	G37E	0.997
7:104207874:G:T	R11S	0.997
7:104136868:A:G	L392P	0.996
7:104161138:T:A	R361S	0.996
7:104161138:T:G	R361S	0.996
7:104161139:C:G	R361T	0.996
7:104166792:C:G	D324H	0.996
7:104166805:A:C	N319K	0.996
7:104166805:A:T	N319K	0.996
7:104166813:A:G	S317P	0.996
7:104166815:G:T	A316D	0.996
7:104166824:G:T	A313E	0.996
7:104166825:C:G	A313P	0.996
7:104166857:A:G	L302P	0.996
7:104184009:A:G	L253P	0.996
7:104184150:A:C	Y236D	0.996
7:104184171:C:G	A229P	0.996
7:104188363:A:G	L191P	0.996

dbSNP variants (sampled 300 via entrez): RS1000006848 (7:104169205 C>T), RS1000064003 (7:104186487 C>T), RS1000065192 (7:104205614 G>C), RS1000075161 (7:104163573 G>A), RS1000113277 (7:104163588 G>A), RS1000158967 (7:104190378 ATC>A), RS1000162875 (7:104147218 C>T), RS1000180553 (7:104171693 A>C), RS1000186104 (7:104162307 G>C), RS1000253123 (7:104198461 C>T), RS1000290635 (7:104165566 C>T), RS1000306222 (7:104203599 G>A), RS1000380235 (7:104203779 G>A), RS1000380718 (7:104154493 T>C), RS1000486624 (7:104160655 G>A)

Disease associations

OMIM: gene MIM:602331 | 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
GCST003542_194	Night sleep phenotypes	3.000000e-06
GCST007328_68	Alcohol consumption (drinks per week)	4.000000e-09
GCST008761_2	Sucrose liking	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010157	sucrose liking measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725187 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
sodium arsenite	decreases expression	1
beta-methylcholine	affects expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Cannabidiol	increases expression	1
Dinitrochlorobenzene	affects binding	1
Estradiol	affects expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Dihydrotestosterone	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Valproic Acid	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Particulate Matter	increases 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
CHEMBL5697628	Binding	Inhibition of ORC5L (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.