RPA4

Summary

RPA4 (replication protein A4, HGNC:30305) is a protein-coding gene on chromosome Xq21.33, encoding Replication protein A 30 kDa subunit (Q13156). As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair.

This gene encodes a single-stranded DNA-binding protein that is the 30-kDa subunit of the replication protein A complex. Replication protein A is an essential factor for DNA double-strand break repair and cell cycle checkpoint activation. The encoded protein localizes to DNA repair foci and may be involved in the cellular DNA damage response. This protein may also play a role in inhibiting viral replication.

Source: NCBI Gene 29935 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 3 total
• MANE Select transcript: NM_013347

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30305
Approved symbol	RPA4
Name	replication protein A4
Location	Xq21.33
Locus type	gene with protein product
Status	Approved
Aliases	HSU24186
Ensembl gene	ENSG00000204086
Ensembl biotype	protein_coding
OMIM	300767
Entrez	29935

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000373040

RefSeq mRNA: 1 — MANE Select: NM_013347 NM_013347

CCDS: CCDS35345

Canonical transcript exons

ENST00000373040 — 1 exons

Exon	Start	End
ENSE00001459388	96883908	96885467

Expression profiles

Bgee: expression breadth ubiquitous, 111 present calls, max score 86.44.

Top tissues by expression

241 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	86.44	silver quality
secondary oocyte	CL:0000655	82.62	gold quality
buccal mucosa cell	CL:0002336	80.40	gold quality
skin of hip	UBERON:0001554	61.25	gold quality
visceral pleura	UBERON:0002401	60.20	silver quality
parietal pleura	UBERON:0002400	60.08	silver quality
pleura	UBERON:0000977	59.71	silver quality
cranial nerve II	UBERON:0000941	58.21	silver quality
granulocyte	CL:0000094	57.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	55.98	gold quality
bone marrow	UBERON:0002371	55.78	silver quality
calcaneal tendon	UBERON:0003701	55.56	silver quality
tibia	UBERON:0000979	55.55	silver quality
pancreatic ductal cell	CL:0002079	55.24	silver quality
oocyte	CL:0000023	55.05	gold quality
bone marrow cell	CL:0002092	54.45	gold quality
lower esophagus mucosa	UBERON:0035834	53.83	gold quality
monocyte	CL:0000576	53.70	gold quality
mononuclear cell	CL:0000842	53.66	gold quality
ileal mucosa	UBERON:0000331	53.08	silver quality
placenta	UBERON:0001987	52.71	gold quality
leukocyte	CL:0000738	52.60	gold quality
male germ cell	CL:0000015	51.92	gold quality
sperm	CL:0000019	51.75	gold quality
tendon	UBERON:0000043	51.41	silver quality
stromal cell of endometrium	CL:0002255	50.98	silver quality
left testis	UBERON:0004533	50.95	gold quality
right testis	UBERON:0004534	50.63	gold quality
epithelial cell of pancreas	CL:0000083	50.37	gold quality
urethra	UBERON:0000057	50.31	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting RPA4, 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-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-6755-3P	98.61	66.90	834
HSA-MIR-7850-5P	98.12	67.28	1111
HSA-MIR-4772-3P	98.04	65.60	1203
HSA-MIR-503-5P	97.87	66.83	575
HSA-MIR-449C-3P	97.75	67.86	462
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-4540	96.90	67.46	473
HSA-MIR-193A-5P	95.70	65.33	613

Literature-anchored findings (GeneRIF, showing 3)

• Hyperphosphorylated replication protein A is preferentially localized to double-stranded break repair and the DNA damage checkpoint complexes in response to DNA damage. (PMID:15929725)
• Results suggest that RPA4 cannot support cell proliferation but can support processes that maintain the genomic integrity of the cell. (PMID:19942684)
• Findings provide the first direct evidence for the function of alternative form of RPA in human DNA metabolism and support a model for aRPA functioning in chromosome maintenance functions in nonproliferating cells. (PMID:19996105)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	RPA2	FBGN0288834
caenorhabditis_elegans	rpa-2	WBGENE00019767

Paralogs (2): STN1 (ENSG00000107960), RPA2 (ENSG00000117748)

Protein

Protein identifiers

Replication protein A 30 kDa subunit — Q13156 (reviewed: Q13156)

Alternative names: Replication factor A protein 4

All UniProt accessions (1): Q13156

UniProt curated annotations — full annotation on UniProt →

Function. As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA polymerase delta synthesis in the presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange.

Subunit / interactions. Component of the aRPA, the alternative replication protein A complex, a trimeric complex similar to the replication protein A complex/RPA but where RPA1 and RPA3 are associated with RPA4 instead of RPA2. Interacts with RPA1 and RPA3.

Subcellular location. Nucleus.

Tissue specificity. Preferentially expressed in placental and colon mucosa. Widely expressed at intermediate or lower levels.

Similarity. Belongs to the replication factor A protein 2 family.

RefSeq proteins (1): NP_037479* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR014646	Rfa2/RPA32	Family
IPR014892	RPA_C	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR040260	RFA2-like	Family

Pfam: PF08784

UniProt features (5 total): chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13156-F1	81.52	0.55

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-68962	Activation of the pre-replicative complex

MSigDB gene sets: 74 (showing top): REACTOME_DNA_REPLICATION, GOBP_CELL_CYCLE_DNA_REPLICATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, KAUFFMANN_DNA_REPAIR_GENES, KEGG_HOMOLOGOUS_RECOMBINATION, GOCC_NUCLEAR_REPLICATION_FORK, GOBP_NUCLEOTIDE_EXCISION_REPAIR, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, KEGG_MISMATCH_REPAIR, GOBP_DNA_DAMAGE_RESPONSE, GOBP_SIGNAL_TRANSDUCTION_IN_RESPONSE_TO_DNA_DAMAGE, GOBP_CELL_CYCLE_CHECKPOINT_SIGNALING, GOBP_REGULATION_OF_CELL_CYCLE_PHASE_TRANSITION

GO Biological Process (8): DNA damage checkpoint signaling (GO:0000077), double-strand break repair via homologous recombination (GO:0000724), DNA replication (GO:0006260), DNA replication initiation (GO:0006270), DNA repair (GO:0006281), nucleotide-excision repair (GO:0006289), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (4): single-stranded DNA binding (GO:0003697), telomeric repeat DNA binding (GO:0042162), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), DNA replication factor A complex (GO:0005662), site of double-strand break (GO:0035861)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
DNA Replication Pre-Initiation	1
G1/S Transition	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	4
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
recombinational repair	1
double-strand break repair	1
DNA biosynthetic process	1
DNA-templated DNA replication	1
DNA damage response	1
DNA repair	1
cellular response to stress	1
DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear replisome	1
nuclear protein-containing complex	1
site of DNA damage	1

Protein interactions and networks

STRING

1415 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPA4	RPA3	P35244	996
RPA4	GTF2H2C	Q6P1K8	460
RPA4	MMS19	Q96T76	423
RPA4	Q15513	Q15513	419
RPA4	EME2	A4GXA9	394
RPA4	RAD51	Q06609	392
RPA4	ERCC4	Q92889	382
RPA4	RAD52	P43351	380
RPA4	GTF2H2	Q13888	377
RPA4	FAM9C	Q8IZT9	373
RPA4	A0A087WUM3	A0A087WUM3	370
RPA4	XPA	P23025	358
RPA4	EXO1	Q9UQ84	356
RPA4	TOP3A	Q13472	355
RPA4	EGR1	P18146	353
RPA4	GRB14	Q14449	353

IntAct

16 interactions, top by confidence:

A	B	Type	Score
RPA1	RPA3	psi-mi:“MI:0914”(association)	0.920
RPA1	RPA4	psi-mi:“MI:0915”(physical association)	0.740
RPA4	RPA1	psi-mi:“MI:0914”(association)	0.740
RPA3	RPA4	psi-mi:“MI:0915”(physical association)	0.660
RPA4	PTRHD1	psi-mi:“MI:0915”(physical association)	0.560
RPA4	PARP1	psi-mi:“MI:0914”(association)	0.350
	RPA1	psi-mi:“MI:0914”(association)	0.350
ADRM1	POTEF	psi-mi:“MI:0914”(association)	0.350
PTRHD1	RPA4	psi-mi:“MI:0915”(physical association)	0.000
RPA4	katG	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (483): RPA4 (Two-hybrid), RPA3 (Affinity Capture-MS), RPA1 (Affinity Capture-MS), XPC (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), PARP2 (Affinity Capture-MS), PARP1 (Affinity Capture-MS), SSRP1 (Affinity Capture-MS), HMCES (Affinity Capture-MS), RPA4 (Two-hybrid), HMCES (Affinity Capture-MS), XPC (Affinity Capture-MS), PARP2 (Affinity Capture-MS), RPA1 (Affinity Capture-MS), RPA3 (Affinity Capture-MS)

ESM2 similar proteins: A1L2H9, B8AZ14, B9FKM7, F4JSG3, O00267, O55201, O97472, P15927, P22336, P26754, P27894, P34552, Q09236, Q10Q08, Q13156, Q19537, Q21338, Q22307, Q23697, Q26454, Q43704, Q5F310, Q5R405, Q5RC43, Q5ZI08, Q62193, Q63528, Q65XV7, Q6DFS2, Q6FQE9, Q6H7J5, Q6IP18, Q6K9U2, Q6YZ49, Q84K16, Q8LFJ8, Q92372, Q92373, Q99128, Q9DDT5

Diamond homologs: A1L2H9, P15927, Q13156, Q5RC43, Q5Z8L1, Q62193, Q63528, Q6DFS2, Q6IP18, Q6K9U2, Q92373, Q8LFJ8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RAD23B	“up-regulates activity”	RPA4	binding
RPA4	up-regulates	Nucleotide-excision_repair

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

388 predictions. Top by Δscore:

Variant	Effect	Δscore
X:96885141:GCT:G	donor_gain	0.9500
X:96885019:G:GT	donor_gain	0.9300
X:96885144:G:GG	donor_gain	0.8800
X:96885099:C:T	donor_gain	0.8700
X:96884198:A:AG	acceptor_gain	0.8600
X:96884199:G:GG	acceptor_gain	0.8600
X:96884164:CAG:C	acceptor_gain	0.8400
X:96884162:CTCAG:C	acceptor_gain	0.8000
X:96884163:TCAG:T	acceptor_gain	0.8000
X:96884165:A:T	acceptor_gain	0.7800
X:96884755:G:C	acceptor_gain	0.7700
X:96885072:G:GT	donor_gain	0.7700
X:96885103:G:T	donor_gain	0.7400
X:96884166:G:T	acceptor_gain	0.7000
X:96885139:CAGCT:C	donor_gain	0.7000
X:96885140:AGCT:A	donor_gain	0.6900
X:96885141:GCTG:G	donor_gain	0.6900
X:96885142:CT:C	donor_gain	0.6600
X:96884171:CCAG:C	acceptor_gain	0.6400
X:96884172:CAG:C	acceptor_gain	0.6400
X:96884173:AGCA:A	acceptor_gain	0.6400
X:96884174:G:T	acceptor_gain	0.6400
X:96885174:G:GT	donor_gain	0.6400
X:96884139:GGTA:G	acceptor_gain	0.6200
X:96885147:A:AG	donor_gain	0.6200
X:96885148:G:GG	donor_gain	0.6200
X:96884020:TGGGA:T	acceptor_gain	0.6100
X:96884199:GCTC:G	acceptor_gain	0.5900
X:96884193:C:CA	acceptor_gain	0.5700
X:96884134:CCACA:C	acceptor_loss	0.5500

AlphaMissense

1734 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:96885079:T:C	F257L	0.933
X:96885081:T:A	F257L	0.933
X:96885081:T:G	F257L	0.933
X:96884542:G:T	G78W	0.931
X:96884800:G:C	A164P	0.921
X:96885022:G:C	A238P	0.921
X:96884531:T:A	V74D	0.918
X:96884471:T:A	L54H	0.914
X:96884543:G:A	G78E	0.909
X:96884500:T:C	F64L	0.908
X:96884502:C:A	F64L	0.908
X:96884502:C:G	F64L	0.908
X:96884598:T:A	D96E	0.903
X:96884598:T:G	D96E	0.903
X:96884696:G:A	G129D	0.903
X:96884684:T:A	V125D	0.900
X:96884688:A:C	K126N	0.898
X:96884688:A:T	K126N	0.898
X:96884729:T:A	L140H	0.898
X:96884533:T:C	S75P	0.889
X:96884978:T:A	L223H	0.888
X:96884584:T:G	Y92D	0.886
X:96885084:G:C	K258N	0.885
X:96885084:G:T	K258N	0.885
X:96884690:T:A	V127E	0.884
X:96884924:T:A	V205E	0.882
X:96885080:T:C	F257S	0.873
X:96884549:T:C	I80T	0.872
X:96884549:T:G	I80S	0.872
X:96884978:T:C	L223P	0.872

dbSNP variants (sampled 300 via entrez): RS1000555720 (X:96883672 G>A,T), RS1000904128 (X:96883903 G>A), RS1000934881 (X:96883513 T>C), RS1002901531 (X:96884022 G>C), RS1004160536 (X:96882983 A>C,G), RS1004795656 (X:96884184 G>A), RS1004904274 (X:96882442 A>G), RS1005836154 (X:96884900 A>T), RS1006365109 (X:96883081 A>G), RS1006434061 (X:96882832 G>A), RS1006465025 (X:96882583 G>A), RS1006658486 (X:96885184 TAAA>T,TA,TAA,TAAAA,TAAAAA), RS1007557069 (X:96882457 T>G), RS1010073336 (X:96885749 T>C), RS1010196864 (X:96883711 C>G,T)

Disease associations

OMIM: gene MIM:300767 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	increases methylation	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
butyraldehyde	increases methylation	1
caprylic aldehyde	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentanal	increases methylation	1
heptanal	increases methylation	1
chromium hexavalent ion	decreases expression	1
abrine	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Lipopolysaccharides	increases expression, affects response to substance	1
Ozone	increases abundance, affects expression	1
Plant Oils	increases expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Asbestos, Serpentine	increases expression	1

Clinical trials (associated diseases)

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