RPAIN

Summary

RPAIN (RPA interacting protein, HGNC:28641) is a protein-coding gene on chromosome 17p13.2, encoding RPA-interacting protein (Q86UA6). Mediates the import of RPA complex into the nucleus, possibly via some interaction with importin beta. It is a common-essential gene (DepMap: required in 96.4% of cancer cell lines).

Predicted to enable zinc ion binding activity. Acts upstream of or within protein import into nucleus and response to UV. Located in PML body; cytoplasm; and fibrillar center.

Source: NCBI Gene 84268 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 49 total
• Cancer dependency (DepMap): dependent in 96.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_001033002

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28641
Approved symbol	RPAIN
Name	RPA interacting protein
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC4189, RIP, hRIP
Ensembl gene	ENSG00000129197
Ensembl biotype	protein_coding
OMIM	617299
Entrez	84268

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 13 protein_coding, 6 retained_intron, 5 nonsense_mediated_decay

ENST00000327154, ENST00000381208, ENST00000381209, ENST00000405578, ENST00000536255, ENST00000539417, ENST00000570883, ENST00000571043, ENST00000571558, ENST00000571613, ENST00000572174, ENST00000573126, ENST00000573577, ENST00000574003, ENST00000575112, ENST00000575599, ENST00000575711, ENST00000876814, ENST00000916148, ENST00000916149, ENST00000916150, ENST00000916151, ENST00000951884, ENST00000951885

RefSeq mRNA: 5 — MANE Select: NM_001033002 NM_001033002, NM_001160243, NM_001160244, NM_001160246, NM_001160266

CCDS: CCDS32536, CCDS54075, CCDS54076, CCDS54077, CCDS54079

Canonical transcript exons

ENST00000381209 — 7 exons

Exon	Start	End
ENSE00000887178	5425971	5426082
ENSE00003522507	5426236	5426299
ENSE00003585834	5421296	5421466
ENSE00003615596	5422769	5422829
ENSE00003665665	5428071	5428211
ENSE00003913363	5420182	5420291
ENSE00003914954	5432542	5432877

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 97.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.8168 / max 611.6096, expressed in 1820 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159033	36.9313	1818
159032	8.1182	1777
159030	0.4006	118
159031	0.2110	64
159034	0.1556	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	97.66	gold quality
ganglionic eminence	UBERON:0004023	97.31	gold quality
middle temporal gyrus	UBERON:0002771	94.37	gold quality
adenohypophysis	UBERON:0002196	93.38	gold quality
ventricular zone	UBERON:0003053	93.28	gold quality
sperm	CL:0000019	93.10	gold quality
left ovary	UBERON:0002119	93.09	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.94	gold quality
pituitary gland	UBERON:0000007	92.87	gold quality
right ovary	UBERON:0002118	92.67	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.56	gold quality
gastrocnemius	UBERON:0001388	92.55	gold quality
prefrontal cortex	UBERON:0000451	92.52	gold quality
mucosa of stomach	UBERON:0001199	92.38	gold quality
muscle of leg	UBERON:0001383	92.22	gold quality
anterior cingulate cortex	UBERON:0009835	91.80	gold quality
nucleus accumbens	UBERON:0001882	91.66	gold quality
cingulate cortex	UBERON:0003027	91.63	gold quality
right atrium auricular region	UBERON:0006631	91.59	gold quality
endothelial cell	CL:0000115	91.57	gold quality
left adrenal gland cortex	UBERON:0035825	91.46	gold quality
calcaneal tendon	UBERON:0003701	91.42	gold quality
granulocyte	CL:0000094	91.39	gold quality
minor salivary gland	UBERON:0001830	91.35	gold quality
skin of abdomen	UBERON:0001416	91.33	gold quality
primary visual cortex	UBERON:0002436	91.33	gold quality
rectum	UBERON:0001052	91.30	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.29	gold quality
ovary	UBERON:0000992	91.27	gold quality
left adrenal gland	UBERON:0001234	91.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.20
E-CURD-114	yes	8.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting RPAIN, 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-568	99.98	69.86	2084
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-2681-3P	98.18	65.28	577
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-5196-3P	97.57	65.98	979
HSA-MIR-2278	97.30	66.19	1130
HSA-MIR-4793-5P	96.88	65.90	872
HSA-MIR-4435	95.90	65.47	1201
HSA-MIR-4268	94.45	64.09	819

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 4)

• hRIPbeta localises to the PML nuclear body and transports replication protein A (PML) into the PML nuclear body and releases RPA upon UV irradiation. (PMID:16135809)
• The results show that DDX3, eIF5A, and hRIP enhance HIV-1 internal ribosomal entry site-mediated translation. (PMID:21360055)
• hRIPalpha is involved in cell proliferation through regulation of RPA transport (PMID:23010595)
• Suggest that increased RPAIN levels may contribute to the development of preeclampsia through regulating trophoblast invasion and apoptosis via C1q. (PMID:28032589)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rpain	ENSDARG00000063021
mus_musculus	Rpain	ENSMUSG00000018449
rattus_norvegicus	Rpain	ENSRNOG00000006913
drosophila_melanogaster	Ripalpha	FBGN0032189

Protein

Protein identifiers

RPA-interacting protein — Q86UA6 (reviewed: Q86UA6)

All UniProt accessions (2): Q86UA6, B3KTT3

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the import of RPA complex into the nucleus, possibly via some interaction with importin beta. Isoform 2 is sumoylated and mediates the localization of RPA complex into the PML body of the nucleus, thereby participating in RPA function in DNA metabolism.

Subunit / interactions. Interacts with the RPA1 subunit of RPA complex.

Subcellular location. Cytoplasm. Nucleus Nucleus. PML body.

Tissue specificity. Widely expressed. Expressed in pancreas, kidney, muscle, liver, lung, placenta, brain, heart, leukocytes, colon, intestine, ovary, testis, prostate, thymus and spleen.

Post-translational modifications. Sumoylated. Sumoylation is required for localization in the nuclear PML body and transport of RPA complex in PML body. Upon UV irradiation and during S phase, it is desumoylated, releasing RPA complex that is translocated to sites of DNA damage. Sumoylation takes place at different Lys residues. Variant ‘Lys-103’ adds a sumoylation site and increases total sumoylation levels.

Miscellaneous. Major isoform with isoform 2. Major isoform with isoform 1. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be due to an intron retention. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (9)

UniProt ID	Names	Canonical?
Q86UA6-1	1, Alpha, hRIPalpha	yes
Q86UA6-2	2, Beta, hRIPbeta
Q86UA6-3	3, Gamma2
Q86UA6-4	4, Gamma1
Q86UA6-5	5, Delta2
Q86UA6-6	6, Delta3
Q86UA6-7	7, Delta1, Delta 4
Q86UA6-8	8
Q86UA6-9	9

RefSeq proteins (5): NP_001028174, NP_001153715, NP_001153716, NP_001153718, NP_001153738 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028155	RPA_interact_central	Domain
IPR028156	RIP	Family
IPR028158	RPA_interact_N_dom	Domain
IPR028159	RPA_interact_C_dom	Domain

Pfam: PF14766, PF14767, PF14768

UniProt features (20 total): splice variant 11, mutagenesis site 3, chain 1, zinc finger region 1, sequence variant 1, region of interest 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UA6-F1	82.18	0.44

Functional residue map

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

Post-translational modifications (2): 18, 121

Mutagenesis-validated functional residues (3):

Position	Phenotype
114	abolishes sumoylation; when associated with r-121 and r-142.
121	induces a strong decrease in sumoylation; when associated with n-103. abolishes sumoylation; when associated with r-114
142	abolishes sumoylation; when associated with r-114 and r-121.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 111 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GCANCTGNY_MYOD_Q6, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_NUCLEAR_TRANSPORT, MODULE_206, GOBP_RESPONSE_TO_UV, GOBP_RESPONSE_TO_RADIATION, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, E12_Q6

GO Biological Process (2): protein import into nucleus (GO:0006606), response to UV (GO:0009411)

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), PML body (GO:0016605)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
response to light stimulus	1
transition metal ion binding	1
binding	1
cation binding	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear body	1

Protein interactions and networks

STRING

840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPAIN	XPO1	O14980	562
RPAIN	EPS15	P42566	490
RPAIN	ETAA1	Q9NY74	489
RPAIN	ITSN2	Q9NZM3	462
RPAIN	POLD2	P49005	459
RPAIN	ITSN1	Q15811	447
RPAIN	AGFG1	P52594	443
RPAIN	ANAPC16	Q96DE5	440
RPAIN	TELO2	Q9Y4R8	408
RPAIN	CRIP1	P50238	405
RPAIN	KHDRBS1	Q07666	390
RPAIN	RNASEH1	O60930	388
RPAIN	NUP42	O15504	385
RPAIN	USP1	O94782	385
RPAIN	CRIP2	P52943	379

IntAct

10 interactions, top by confidence:

A	B	Type	Score
RAD51B	RPAIN	psi-mi:“MI:0915”(physical association)	0.560
RPAIN	ADH6	psi-mi:“MI:0915”(physical association)	0.370
CYP17A1	RPAIN	psi-mi:“MI:0915”(physical association)	0.370
GSTA1	RPAIN	psi-mi:“MI:0915”(physical association)	0.370
CDCA5	RPAIN	psi-mi:“MI:0915”(physical association)	0.370
RPAIN	RPA2	psi-mi:“MI:0914”(association)	0.350
RPAIN	OXSR1	psi-mi:“MI:0914”(association)	0.350
RAD51B	RPAIN	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (25): RPA1 (Affinity Capture-MS), RPA2 (Affinity Capture-MS), UBR7 (Affinity Capture-MS), RPAIN (Two-hybrid), RPAIN (Two-hybrid), RPA1 (Affinity Capture-MS), UBR7 (Affinity Capture-MS), RPAIN (Affinity Capture-RNA), RPAIN (Affinity Capture-RNA), RAD51B (Two-hybrid), RPA1 (Affinity Capture-MS), RPA2 (Affinity Capture-MS), PDXDC1 (Affinity Capture-MS), BANP (Affinity Capture-MS), OXSR1 (Affinity Capture-MS)

ESM2 similar proteins: A0PJT0, D3ZND0, D4A4K3, G9G127, I1VZH0, O60826, O75800, P86182, Q1RMI8, Q1T769, Q1T7C1, Q24JY3, Q28G12, Q2TBK4, Q2YD98, Q4V909, Q503N2, Q5REX6, Q5XGL1, Q61043, Q67XT3, Q6AXZ5, Q6NRW3, Q6NVC9, Q6NY52, Q6P8A1, Q6PA15, Q6PA69, Q6ZNE5, Q7SYB5, Q7TMK6, Q80YF0, Q86UA6, Q8BHX1, Q8BIJ7, Q8C2K1, Q8C3S2, Q8CDJ3, Q8N4C6, Q8NBT2

Diamond homologs: Q4G2Y1, Q5M782, Q86UA6, Q9CWY9, Q9W704

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1041 predictions. Top by Δscore:

Variant	Effect	Δscore
17:5421295:GAGAT:G	acceptor_gain	1.0000
17:5422766:CA:C	acceptor_loss	1.0000
17:5422767:A:AG	acceptor_gain	1.0000
17:5422767:AGC:A	acceptor_loss	1.0000
17:5422767:AGCT:A	acceptor_gain	1.0000
17:5422768:G:A	acceptor_loss	1.0000
17:5422768:G:GA	acceptor_gain	1.0000
17:5422768:GCTG:G	acceptor_gain	1.0000
17:5422827:AAGG:A	donor_loss	1.0000
17:5422830:G:C	donor_loss	1.0000
17:5426083:G:GG	donor_gain	1.0000
17:5419574:C:CT	acceptor_gain	0.9900
17:5419831:G:T	donor_gain	0.9900
17:5419832:A:T	donor_gain	0.9900
17:5420289:CAG:C	donor_loss	0.9900
17:5420290:AG:A	donor_loss	0.9900
17:5420291:GG:G	donor_loss	0.9900
17:5420292:G:C	donor_loss	0.9900
17:5421275:A:AG	acceptor_gain	0.9900
17:5421291:CCCA:C	acceptor_loss	0.9900
17:5421293:CA:C	acceptor_loss	0.9900
17:5421294:A:AG	acceptor_gain	0.9900
17:5421295:G:GG	acceptor_gain	0.9900
17:5421295:GA:G	acceptor_gain	0.9900
17:5421295:GAGA:G	acceptor_gain	0.9900
17:5421462:CTCAG:C	donor_loss	0.9900
17:5421463:TCAG:T	donor_loss	0.9900
17:5421464:CAG:C	donor_loss	0.9900
17:5421465:AG:A	donor_loss	0.9900
17:5421466:GG:G	donor_loss	0.9900

AlphaMissense

1444 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:5426066:T:C	C137R	0.996
17:5428158:T:C	F193L	0.993
17:5428159:T:C	F193S	0.993
17:5428160:T:A	F193L	0.993
17:5428160:T:G	F193L	0.993
17:5426270:T:C	C154R	0.991
17:5428206:T:C	C209R	0.988
17:5426075:T:C	C140R	0.987
17:5426068:T:G	C137W	0.986
17:5426077:T:G	C140W	0.983
17:5420284:T:C	F25S	0.982
17:5426272:T:G	C154W	0.982
17:5428208:T:G	C209W	0.982
17:5432546:G:A	C212Y	0.981
17:5422818:T:C	L101P	0.980
17:5426067:G:A	C137Y	0.980
17:5426075:T:A	C140S	0.980
17:5426076:G:C	C140S	0.980
17:5428140:T:C	C187R	0.979
17:5432545:T:C	C212R	0.979
17:5421347:C:A	R45S	0.978
17:5426066:T:A	C137S	0.978
17:5426067:G:C	C137S	0.978
17:5426076:G:A	C140Y	0.977
17:5432547:T:G	C212W	0.977
17:5426271:G:A	C154Y	0.976
17:5420283:T:C	F25L	0.974
17:5420285:C:A	F25L	0.974
17:5420285:C:G	F25L	0.974
17:5428159:T:G	F193C	0.974

dbSNP variants (sampled 300 via entrez): RS1000497587 (17:5429077 TCATTAA>T), RS1000595902 (17:5429664 A>G), RS1000649961 (17:5429276 C>T), RS1000811065 (17:5422386 C>G,T), RS1001097745 (17:5422095 C>A,T), RS1001649243 (17:5423921 T>A), RS1001940878 (17:5430360 G>A,T), RS1001988006 (17:5432180 G>A), RS1002002887 (17:5430941 G>A,T), RS1002329249 (17:5419423 G>A,C), RS1003063757 (17:5420194 T>C), RS1003215735 (17:5420483 T>C), RS1003400798 (17:5419072 C>G,T), RS1003634208 (17:5432943 C>T), RS1003650950 (17:5427075 A>G)

Disease associations

OMIM: gene MIM:617299 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005312_38	Menopause (age at onset)	2.000000e-09
GCST008129_88	Body mass index	5.000000e-10
GCST90002398_260	Neutrophil count	3.000000e-14
GCST90002407_570	White blood cell count	2.000000e-21

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0004340	body mass index
EFO:0004833	neutrophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, increases expression, affects cotreatment	7
methylmercuric chloride	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
moringin	affects cotreatment, decreases expression	1
dicrotophos	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
beta-lapachone	decreases expression, increases expression	1
manganese chloride	decreases expression, increases abundance	1
N-benzyloxycarbonylprolylprolinal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
entinostat	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
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Cannabidiol	affects cotreatment, decreases expression	1
Demecolcine	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	increases expression	1
Manganese	decreases expression, increases abundance	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1
Vincristine	decreases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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