RPA2

Summary

RPA2 (replication protein A2, HGNC:10290) is a protein-coding gene on chromosome 1p35.3, encoding Replication protein A 32 kDa subunit (P15927). As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates that form during DNA replication or upon DNA stress.

This gene encodes a subunit of the heterotrimeric Replication Protein A (RPA) complex, which binds to single-stranded DNA (ssDNA), forming a nucleoprotein complex that plays an important role in DNA metabolism, being involved in DNA replication, repair, recombination, telomere maintenance, and co-ordinating the cellular response to DNA damage through activation of the ataxia telangiectasia and Rad3-related protein (ATR) kinase. The RPA complex protects single-stranded DNA from nucleases, prevents formation of secondary structures that would interfere with repair, and co-ordinates the recruitment and departure of different genome maintenance factors. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which oligonucleotide/oligosaccharide-binding (OB) domains of the complex are utilized, and differing in the length of DNA bound. This subunit contains a single OB domain that participates in high-affinity DNA binding and also contains a winged helix domain at its carboxy terminus, which interacts with many genome maintenance protein. Post-translational modifications of the RPA complex also plays a role in co-ordinating different damage response pathways.

Source: NCBI Gene 6118 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 53 total
• Druggable target: yes
• MANE Select transcript: NM_002946

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10290
Approved symbol	RPA2
Name	replication protein A2
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000117748
Ensembl biotype	protein_coding
OMIM	179836
Entrez	6118

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000313433, ENST00000373909, ENST00000373912, ENST00000419958, ENST00000444045, ENST00000882504, ENST00000882505, ENST00000882506, ENST00000882507, ENST00000935485, ENST00000935486

RefSeq mRNA: 5 — MANE Select: NM_002946 NM_001286076, NM_001297558, NM_001355128, NM_001355129, NM_002946

CCDS: CCDS314, CCDS72740

Canonical transcript exons

ENST00000373912 — 9 exons

Exon	Start	End
ENSE00000761795	27897633	27897707
ENSE00000761799	27894290	27894397
ENSE00000761801	27894012	27894106
ENSE00000956216	27907181	27907282
ENSE00000956217	27906928	27907041
ENSE00001065438	27914063	27914169
ENSE00001461899	27891524	27892247
ENSE00001461906	27914434	27914575
ENSE00003785392	27897005	27897121

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.1962 / max 266.3281, expressed in 1815 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11306	33.1398	1814
11307	2.1155	905
11305	0.9409	577

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.11	gold quality
granulocyte	CL:0000094	96.30	gold quality
ganglionic eminence	UBERON:0004023	95.73	gold quality
right testis	UBERON:0004534	95.44	gold quality
left testis	UBERON:0004533	95.01	gold quality
gastrocnemius	UBERON:0001388	94.80	gold quality
muscle of leg	UBERON:0001383	94.73	gold quality
calcaneal tendon	UBERON:0003701	94.67	gold quality
right uterine tube	UBERON:0001302	94.08	gold quality
testis	UBERON:0000473	93.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.64	gold quality
tibialis anterior	UBERON:0001385	93.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.49	gold quality
lymph node	UBERON:0000029	93.03	gold quality
left ovary	UBERON:0002119	92.80	gold quality
gall bladder	UBERON:0002110	92.58	gold quality
prefrontal cortex	UBERON:0000451	92.45	gold quality
right ovary	UBERON:0002118	92.44	gold quality
islet of Langerhans	UBERON:0000006	92.40	gold quality
leukocyte	CL:0000738	92.23	gold quality
right frontal lobe	UBERON:0002810	92.13	gold quality
right coronary artery	UBERON:0001625	92.04	gold quality
blood	UBERON:0000178	91.90	gold quality
spleen	UBERON:0002106	91.90	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.86	gold quality
monocyte	CL:0000576	91.84	gold quality
mononuclear cell	CL:0000842	91.82	gold quality
gluteal muscle	UBERON:0002000	91.74	gold quality
nucleus accumbens	UBERON:0001882	91.69	gold quality
rectum	UBERON:0001052	91.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting RPA2, 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-4487	99.96	64.58	1252
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-943	97.81	64.42	694
HSA-MIR-339-5P	96.73	66.01	820
HSA-MIR-592	96.59	67.59	817
HSA-MIR-549A-5P	96.35	68.08	587

Literature-anchored findings (GeneRIF, showing 38)

• Phosphorylation of the RPA2 subunit is observed after exposure of cells to ionizing radiation (IR) and other DNA-damaging agents, which implicates the modified protein in the regulation of DNA replication after DNA damage or in DNA repair. (PMID:11731442)
• RPA2 binds to menin and has a role in multiple endocrine neoplasia (PMID:12509449)
• C-terminal domain of hRPA32 subunit (RPA32C) facilitates initiation of SV40 replication. (PMID:15793585)
• in response to UV-induced DNA damage, ATR rapidly phosphorylates RPA2, disrupting its association with replication centers in the S-phase and contributing to the inhibition of DNA replication (PMID:17035231)
• Determination at single-nucleotide resolution the relative positions of the single-stranded DNA with interacting intrinsic tryptophans of RPA32. (PMID:17583916)
• RPA phosphorylation facilitates chromosomal DNA repair. (PMID:17928296)
• RPA32 is extensively phosphorylated after the induction of EBV lytic replication. Rad51 and RPA32 are necessary for the completion of EBV lytic infection. (PMID:19386720)
• The N-terminus of RPA1 and phosphorylation of RPA2 regulate RPA interactions with the MRE11-RAD50-NBS1 (MRN) complex and are important in the response to DNA damage. (PMID:19586055)
• mitotic phosphorylation of RPA2 starts at the onset of mitosis, and dephosphorylation occurs during late cytokinesis. (PMID:19671522)
• These data indicate that PP2A-mediated RPA32 dephosphorylation is required for the efficient DNA damage repair. (PMID:19704001)
• RPA32, critical for cell proliferation and maintenance of genome stability, are markedly down-regulated, Data hypothesized that their DNA-related functions could be partially limited in TRAIL-resistant HL-60 cells. (PMID:19834905)
• data suggest that RPA2 hyperphosphorylation plays a critical role in maintenance of genomic stability and cell survival after a DNA replication block via promotion of homologus recombination (PMID:20130019)
• Data suggest that PP4-mediated dephosphorylation of RPA2 is necessary for an efficient DNA-damage response. (PMID:20154705)
• At the subunit level, 13 proteins out of 30 examined may interact with RPA2. (PMID:20679368)
• RPA1 and RPA2 overexpression seems to be more important during early T-categories of bladder carcinogenesis, showing similar kinetics with cyclin D1 (PMID:21062395)
• RPA2 up-regulation may be involved in the growth and/or survival of BRCA1 tumor cells and useful in immunohistochemical discrimination of triple-negative BRCA1 tumors. (PMID:21137066)
• Replication protein A1, replication protein A2, and cyclins D2 and D3 seem to have a parallel role in the promotion of cell cycle in astrocytic tumors being implicated in the malignant progression of these neoplasms. (PMID:21496876)
• RPA2 hyperphosphorylation by DNA-PK in response to DNA double-strand breaks blocks unscheduled homologous recombination and delays mitotic entry. (PMID:21731742)
• Data show that the R88C variant impairs binding of the R88C variant impairs binding of uracil-DNA glycosylase UNG2 to replication protein A RPA2. (PMID:22521144)
• 4E-BP3 regulates eIF4E-mediated nuclear mRNA export and interacts with replication protein A2 (PMID:22684010)
• this study has explored the role of RPA32 phosphorylation at CDK and ATR sites and propose that phosphorylation of the RPA32 subunit is dispensable for checkpoint activation induced by replication stress with aphidicolin. (PMID:23047005)
• study concludes RPA2 expression is translationally regulated via internal ribosome entry site and by eIF3a and that this regulation is partly accountable for cellular response to DNA damage and survival. (PMID:23393223)
• study reports the characterization of the RPA32C-SMARCAL1 interface at the molecular level; implications of results are discussed with respect to the recruitment of SMARCAL1 and other DNA damage response and repair proteins to stalled replication forks (PMID:24730652)
• RPA32 phosphorylation regulates replication arrest, recombination, late origin firing, and mitotic catastrophe (PMID:24819595)
• Conserved motifs are required for RPA32 binding the the N-terminus of SMARCAL1. (PMID:24910198)
• Expression of mutant RPA2 or loss of PALB2 expression led to significant DNA damage after replication stress, a defect accentuated by poly-ADP (adenosine diphosphate) ribose polymerase inhibitors. (PMID:25113031)
• The authors show that Vpr can form a trimolecular complex with UNG2 and RPA32 and the positive effect of UNG2 and RPA32 on the reverse transcription process leading to optimal virus replication and dissemination between the primary target cells of HIV-1. (PMID:27068393)
• knockdown of RPA2 promoted formation of the menin-p65 complex and repressed the expression of NF-kappaB-mediated genes. RPA2 expression was induced via an E2F1-dependent mechanism in MCF7 and MDA-MB-231 cells treated with NF-kappaB activators, TNF-alpha or lipopolysaccharide (LPS). (PMID:28007956)
• RPA, best known for its role in DNA replication and repair, recruits HIRA to promoters and enhancers and regulates deposition of newly synthesized H3.3 to these regulatory elements for gene regulation. (PMID:28107649)
• Single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit interstrand crossling repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. (PMID:28575657)
• E3 ligase RFWD3 functions in timely removal and degradation of RPA and RAD51 to allow homologous recombination progression to subsequent steps following mitomycin C damage. (PMID:28575658)
• HERC2 regulates RPA2 by mediating ATR-induced Ser33 phosphorylation and ubiquitin-dependent degradation. (PMID:31582797)
• Dynamic elements of replication protein A at the crossroads of DNA replication, recombination, and repair. (PMID:32856505)
• RPA2 winged-helix domain facilitates UNG-mediated removal of uracil from ssDNA; implications for repair of mutagenic uracil at the replication fork. (PMID:33784377)
• hSSB2 (NABP1) is required for the recruitment of RPA during the cellular response to DNA UV damage. (PMID:34642383)
• Upregulated RPA2 in endometrial tissues of repeated implantation failure patients impairs the endometrial decidualization. (PMID:37831348)
• CSB and SMARCAL1 compete for RPA32 at stalled forks and differentially control the fate of stalled forks in BRCA2-deficient cells. (PMID:38416570)
• Mechanism of single-stranded DNA annealing by RAD52-RPA complex. (PMID:38658755)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rpa2	ENSDARG00000037188
mus_musculus	Rpa2	ENSMUSG00000028884
rattus_norvegicus	Rpa2	ENSRNOG00000013005

Paralogs (2): STN1 (ENSG00000107960), RPA4 (ENSG00000204086)

Protein

Protein identifiers

Replication protein A 32 kDa subunit — P15927 (reviewed: P15927)

Alternative names: Replication factor A protein 2, Replication protein A 34 kDa subunit

All UniProt accessions (3): P15927, Q5TEJ0, Q5TEJ7

UniProt curated annotations — full annotation on UniProt →

Function. As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage. In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response. It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage. Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair. Also plays a role in base excision repair (BER) probably through interaction with UNG. Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance. RPA stimulates 5’-3’ helicase activity of BRIP1/FANCJ.

Subunit / interactions. Component of the replication protein A complex (RPA/RP-A), a heterotrimeric complex composed of RPA1, RPA2 and RPA3. Interacts with PRPF19; the PRP19-CDC5L complex is recruited to the sites of DNA repair where it ubiquitinates the replication protein A complex (RPA). Interacts with SERTAD3. Interacts with TIPIN. Interacts with TIMELESS. Interacts with PPP4R2; the interaction is direct, DNA damage-dependent and mediates the recruitment of the PP4 catalytic subunit PPP4C. Interacts (hyperphosphorylated) with RAD51. Interacts with SMARCAL1; the interaction is direct and mediates the recruitment to the RPA complex of SMARCAL1. Interacts with RAD52 and XPA; those interactions are direct and associate RAD52 and XPA to the RPA complex. Interacts with FBH1. Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks. Interacts with RFWD3. Interacts with DDI2. Interacts (in unphosphorylated form via N-terminus) with EIF4EBP3; the interaction enhances EIF4EBP3-mediated inhibition of EIF4E-mediated mRNA nuclear export. Interacts with BRIP1/FANCJ via the RPA1 subunit; following DNA damage they colocalize in foci in the nucleus. Interacts with nuclear UNG (isoform 2); this interaction mediates UNG recruitment to RPA-coated single-stranded DNA at stalled replication forks.

Subcellular location. Nucleus. PML body.

Post-translational modifications. Differentially phosphorylated throughout the cell cycle, becoming phosphorylated at the G1-S transition and dephosphorylated in late mitosis. Mainly phosphorylated at Ser-23 and Ser-29, by cyclin A-CDK2 and cyclin B-CDK1, respectively during DNA replication and mitosis. Dephosphorylation may require the serine/threonine-protein phosphatase 4. Phosphorylation at Ser-23 and Ser-29 is a prerequisite for further phosphorylation. Becomes hyperphosphorylated on additional residues including Ser-4, Ser-8, Thr-21 and Ser-33 in response to DNA damage. Hyperphosphorylation is mediated by ATM, ATR and PRKDC. Primarily recruited to DNA repair nuclear foci as a hypophosphorylated form it undergoes subsequent hyperphosphorylation, catalyzed by ATR. Hyperphosphorylation is required for RAD51 recruitment to chromatin and efficient DNA repair. Phosphorylation at Thr-21 depends upon RFWD3 presence. DNA damage-induced ‘Lys-63’-linked polyubiquitination by PRPF19 mediates ATRIP recruitment to the RPA complex at sites of DNA damage and activation of ATR. Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination.

Induction. Translationally up-regulated in response to DNA damage (at protein level).

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

Isoforms (3)

UniProt ID	Names	Canonical?
P15927-1	1	yes
P15927-2	2
P15927-3	3

RefSeq proteins (5): NP_001273005, NP_001284487, NP_001342057, NP_001342058, NP_002937* (*=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 (51 total): strand 13, mutagenesis site 12, modified residue 7, helix 6, sequence variant 3, cross-link 2, splice variant 2, region of interest 2, turn 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
4OU0	X-RAY DIFFRACTION	1.4
4MQV	X-RAY DIFFRACTION	1.95
3KDF	X-RAY DIFFRACTION	1.98
2PI2	X-RAY DIFFRACTION	2
1QUQ	X-RAY DIFFRACTION	2.5
2PQA	X-RAY DIFFRACTION	2.5
1L1O	X-RAY DIFFRACTION	2.8
2Z6K	X-RAY DIFFRACTION	3
8RK2	ELECTRON MICROSCOPY	3.2
9PD3	ELECTRON MICROSCOPY	3.3
9PD4	ELECTRON MICROSCOPY	3.4
9MJ5	ELECTRON MICROSCOPY	3.5
1DPU	SOLUTION NMR
1Z1D	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15927-F1	80.47	0.57

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 (9): 33, 37, 38, 1, 4, 8, 21, 23, 29

Mutagenesis-validated functional residues (12):

Position	Phenotype
4	increased rad51 foci formation and homologous recombination efficiency at dna double-strand breaks; when associated with
8	increased rad51 foci formation and homologous recombination efficiency at dna double-strand breaks; when associated with
8	lower homologous recombination efficiency following dna double strand break. impaired dna synthesis following dna damage
23	no effect on dna synthesis following dna damage; when associated with d-29. no effect on cell-cycle progression, nor dna
29	reduces phosphorylation by cdk1.
29	no effect on dna synthesis following dna damage; when associated with d-23. no effect on cell-cycle progression, nor dna
33	lower homologous recombination efficiency following dna double strand break. impaired dna synthesis following dna damage
37–38	impaired ubiquitination without affecting homologous recombination.
248	abolishes interaction with rfwd3, leading to impair dna interstrand cross-links (icl) repair.
252	abolishes interaction with rfwd3, leading to impair dna interstrand cross-links (icl) repair.
253	does not affect interaction with rfwd3.
254	abolishes interaction with rfwd3, leading to impair dna interstrand cross-links (icl) repair.

Function

Pathways and Gene Ontology

Reactome pathways

29 pathways

ID	Pathway
R-HSA-110312	Translesion synthesis by REV1
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-110320	Translesion Synthesis by POLH
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371511	HSF1 activation
R-HSA-5358565	Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
R-HSA-5358606	Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair
R-HSA-5655862	Translesion synthesis by POLK
R-HSA-5656121	Translesion synthesis by POLI
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-5685938	HDR through Single Strand Annealing (SSA)
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-5696395	Formation of Incision Complex in GG-NER
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-6783310	Fanconi Anemia Pathway
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-68962	Activation of the pre-replicative complex
R-HSA-69166	Removal of the Flap Intermediate
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-912446	Meiotic recombination
R-HSA-9709570	Impaired BRCA2 binding to RAD51

MSigDB gene sets: 367 (showing top): PID_FANCONI_PATHWAY, REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, KALMA_E2F1_TARGETS, REACTOME_DNA_REPLICATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, PAL_PRMT5_TARGETS_UP, FISCHER_G1_S_CELL_CYCLE, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_CELL_CYCLE_PHASE_TRANSITION, KENNY_CTNNB1_TARGETS_UP

GO Biological Process (14): telomere maintenance (GO:0000723), double-strand break repair via homologous recombination (GO:0000724), DNA replication (GO:0006260), base-excision repair (GO:0006284), nucleotide-excision repair (GO:0006289), mismatch repair (GO:0006298), regulation of double-strand break repair via homologous recombination (GO:0010569), mitotic G1 DNA damage checkpoint signaling (GO:0031571), protein localization to chromosome (GO:0034502), regulation of DNA damage checkpoint (GO:2000001), DNA damage checkpoint signaling (GO:0000077), DNA repair (GO:0006281), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (9): damaged DNA binding (GO:0003684), single-stranded DNA binding (GO:0003697), enzyme binding (GO:0019899), protein phosphatase binding (GO:0019903), ubiquitin protein ligase binding (GO:0031625), telomeric repeat DNA binding (GO:0042162), G-rich strand telomeric DNA binding (GO:0098505), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), DNA replication factor A complex (GO:0005662), nuclear body (GO:0016604), PML body (GO:0016605), site of double-strand break (GO:0035861)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	5
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3
Global Genome Nucleotide Excision Repair (GG-NER)	3
Cellular response to heat stress	2
Mismatch Repair	2
DNA Damage Bypass	1
Processive synthesis on the C-strand of the telomere	1
G2/M Checkpoints	1
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
Homologous DNA Pairing and Strand Exchange	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	4
DNA repair	3
DNA binding	2
cellular anatomical structure	2
telomere organization	1
recombinational repair	1
double-strand break repair	1
DNA biosynthetic process	1
regulation of DNA recombination	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair	1
mitotic G1 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G1/S transition checkpoint signaling	1
protein localization to organelle	1
DNA damage checkpoint signaling	1
regulation of cellular response to stress	1
regulation of cell cycle checkpoint	1
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
DNA damage response	1
cellular response to stress	1
protein binding	1
phosphatase binding	1
ubiquitin-like protein ligase binding	1
sequence-specific DNA binding	1
single-stranded telomeric DNA binding	1
nucleic acid binding	1
binding	1
chromosomal region	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear replisome	1
nuclear protein-containing complex	1
nucleoplasm	1
intracellular membraneless organelle	1
nuclear body	1
site of DNA damage	1

Protein interactions and networks

STRING

2329 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPA2	RPA1	P27694	999
RPA2	RPA3	P35244	997
RPA2	XPA	P23025	936
RPA2	RAD52	P43351	934
RPA2	SMARCAL1	Q9NZC9	930
RPA2	PRKDC	P78527	864
RPA2	ATRIP	Q8WXE1	848
RPA2	SERTAD3	Q9UJW9	822
RPA2	CHEK1	O14757	817
RPA2	ATM	Q13315	796
RPA2	XRCC6	P12956	782
RPA2	SERTAD1	Q9UHV2	763
RPA2	TP53BP1	Q12888	733
RPA2	RAD51	Q06609	732
RPA2	XRCC5	P13010	708

IntAct

257 interactions, top by confidence:

A	B	Type	Score
MAX	MYC	psi-mi:“MI:0914”(association)	0.980
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
RPA1	RPA2	psi-mi:“MI:0915”(physical association)	0.960
RPA1	RPA2	psi-mi:“MI:0914”(association)	0.960
RPA2	RPA1	psi-mi:“MI:0915”(physical association)	0.960
RPA1	RPA2	psi-mi:“MI:0407”(direct interaction)	0.960
RPA3	RPA2	psi-mi:“MI:0914”(association)	0.930
RPA3	RPA2	psi-mi:“MI:0407”(direct interaction)	0.930
RPA2	RPA3	psi-mi:“MI:0915”(physical association)	0.930
RPA3	RPA2	psi-mi:“MI:0915”(physical association)	0.930
XPA	RPA2	psi-mi:“MI:0914”(association)	0.920
RPA2	XPA	psi-mi:“MI:0915”(physical association)	0.920
XPA	RPA2	psi-mi:“MI:0915”(physical association)	0.920
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
RB1CC1	ATG13	psi-mi:“MI:0914”(association)	0.820
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
XPC	CETN3	psi-mi:“MI:0914”(association)	0.730

BioGRID (3545): RPA2 (Affinity Capture-MS), RPA2 (Affinity Capture-MS), RPA2 (Affinity Capture-Western), RPA2 (Affinity Capture-Western), RPA2 (Affinity Capture-MS), RPA2 (Two-hybrid), RPA2 (Affinity Capture-MS), RPA3 (Affinity Capture-MS), RPA1 (Affinity Capture-MS), XPC (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), LIG3 (Affinity Capture-MS), PARP2 (Affinity Capture-MS), PARP1 (Affinity Capture-MS), HLTF (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, P26754, Q23697, Q9ZQ19

SIGNOR signaling

23 interactions.

A	Effect	B	Mechanism
ATM	up-regulates	RPA2	phosphorylation
ATM	unknown	RPA2	phosphorylation
PRKDC	up-regulates	RPA2	phosphorylation
PRKDC	unknown	RPA2	phosphorylation
PIAS1	up-regulates	RPA2	sumoylation
PIAS4	up-regulates	RPA2	phosphorylation
RPA2	up-regulates	ATRIP	binding
CDK1	“up-regulates activity”	RPA2	phosphorylation
RPA2	up-regulates	MRE11	binding
RPA2	up-regulates	NBN	binding
ATR	unknown	RPA2	phosphorylation
PRPF19	“up-regulates activity”	RPA2	polyubiquitination
PRKDC	“down-regulates activity”	RPA2	phosphorylation
POT1	“down-regulates activity”	RPA2	binding
ACD	“down-regulates activity”	RPA2	binding
RAD23B	“up-regulates activity”	RPA2	binding
RPA2	up-regulates	Nucleotide-excision_repair

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 171 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
Impaired BRCA2 binding to PALB2	5	19.2×	3e-04
Impaired BRCA2 binding to RAD51	7	18.2×	2e-05
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	5	17.8×	3e-04
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	5	17.8×	3e-04
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	5	17.8×	3e-04
Signaling by NOTCH1 PEST Domain Mutants in Cancer	5	17.1×	3e-04
Signaling by NOTCH1 in Cancer	5	17.1×	3e-04
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	5	17.1×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via nonhomologous end joining	7	20.1×	1e-05
nucleotide-excision repair	7	18.2×	2e-05
replication fork processing	5	14.3×	2e-03
cellular response to ionizing radiation	5	14.0×	2e-03
positive regulation of miRNA transcription	7	13.8×	1e-04
branching involved in ureteric bud morphogenesis	5	12.5×	4e-03
positive regulation of transcription initiation by RNA polymerase II	6	11.1×	2e-03
double-strand break repair	8	11.1×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1146 predictions. Top by Δscore:

Variant	Effect	Δscore
1:27892243:CTTGC:C	acceptor_gain	1.0000
1:27892244:TTGC:T	acceptor_gain	1.0000
1:27892245:TGC:T	acceptor_gain	1.0000
1:27892245:TGCCT:T	acceptor_loss	1.0000
1:27892246:GC:G	acceptor_gain	1.0000
1:27892247:CC:C	acceptor_gain	1.0000
1:27892248:C:A	acceptor_loss	1.0000
1:27892248:C:CC	acceptor_gain	1.0000
1:27892249:T:A	acceptor_loss	1.0000
1:27894006:ACTT:A	donor_loss	1.0000
1:27894007:CT:C	donor_loss	1.0000
1:27894009:TA:T	donor_loss	1.0000
1:27894010:A:AC	donor_gain	1.0000
1:27894010:A:T	donor_loss	1.0000
1:27894011:C:CT	donor_gain	1.0000
1:27894011:CT:C	donor_gain	1.0000
1:27894011:CTT:C	donor_gain	1.0000
1:27894011:CTTG:C	donor_gain	1.0000
1:27894011:CTTGA:C	donor_gain	1.0000
1:27894104:CAC:C	acceptor_gain	1.0000
1:27894107:C:CC	acceptor_gain	1.0000
1:27897001:TCAC:T	donor_loss	1.0000
1:27897002:CA:C	donor_loss	1.0000
1:27897003:A:AC	donor_gain	1.0000
1:27897003:A:AT	donor_loss	1.0000
1:27897003:AC:A	donor_gain	1.0000
1:27897004:C:CT	donor_gain	1.0000
1:27897004:CC:C	donor_gain	1.0000
1:27897004:CCTGG:C	donor_gain	1.0000
1:27897117:TTGTT:T	acceptor_gain	1.0000

AlphaMissense

1798 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:27892210:A:C	Y256D	1.000
1:27892218:C:T	G253E	1.000
1:27892219:C:A	G253W	1.000
1:27892219:C:G	G253R	1.000
1:27892219:C:T	G253R	1.000
1:27892230:A:G	L249P	1.000
1:27894070:C:G	G224R	1.000
1:27894070:C:T	G224R	1.000
1:27897102:G:T	A143D	1.000
1:27897636:A:C	F135L	1.000
1:27897636:A:T	F135L	1.000
1:27897638:A:G	F135L	1.000
1:27897652:C:T	G130D	1.000
1:27897653:C:G	G130R	1.000
1:27906940:C:A	W107C	1.000
1:27906940:C:G	W107C	1.000
1:27906941:C:G	W107S	1.000
1:27906942:A:G	W107R	1.000
1:27906942:A:T	W107R	1.000
1:27906950:A:T	V104D	1.000
1:27907028:C:T	G78E	1.000
1:27907029:C:A	G78W	1.000
1:27907029:C:G	G78R	1.000
1:27907029:C:T	G78R	1.000
1:27892184:A:C	F264L	0.999
1:27892184:A:T	F264L	0.999
1:27892185:A:G	F264S	0.999
1:27892186:A:G	F264L	0.999
1:27892188:T:G	H263P	0.999
1:27892189:G:C	H263D	0.999

dbSNP variants (sampled 300 via entrez): RS1000118563 (1:27902353 C>T), RS1000205853 (1:27903962 C>G,T), RS1000212369 (1:27915877 C>T), RS1000431 (1:27898603 C>A,G,T), RS1000432 (1:27898608 T>C), RS1000666602 (1:27910926 C>T), RS1000983385 (1:27896507 A>G), RS1000993148 (1:27896790 G>C), RS1001465050 (1:27906406 G>C), RS1001585009 (1:27913619 T>C), RS1001590869 (1:27894008 T>A,C), RS1001640199 (1:27912828 G>A), RS1001671478 (1:27912489 C>T), RS1001917010 (1:27911899 T>C), RS1001975114 (1:27913300 G>A)

Disease associations

OMIM: gene MIM:179836 | 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
GCST010242_88	HDL cholesterol levels	3.000000e-08
GCST90002400_21	Plateletcrit	8.000000e-17
GCST90002402_537	Platelet count	7.000000e-21
GCST90002407_393	White blood cell count	3.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007985	platelet crit
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196071 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, decreases expression	3
Carbamazepine	affects expression	2
Cyclosporine	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
RGFP966	affects reaction, increases phosphorylation	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
4-biphenylamine	increases expression, decreases reaction	1
bisphenol A	decreases methylation, affects cotreatment	1
methylselenic acid	decreases expression	1
tetrahydropalmatine	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	increases phosphorylation	1
veliparib	decreases reaction, increases expression	1
quizartinib	affects reaction, increases phosphorylation	1
riccardin D	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
picoxystrobin	increases expression	1
CX 5461	increases phosphorylation, affects reaction	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Troglitazone	decreases expression	1
Artesunate	increases phosphorylation	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6101753	Binding	Inhibition of RPA32 phosphorylation in human MDA-MB-436 cells at 20 to 500 nM incubated for 24 hrs by Western blot analysis	Discovery and Optimization of a Series of Novel Morpholine-Containing USP1 Inhibitors. — J Med Chem

Clinical trials (associated diseases)

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