RPA1 (RPA70) - the large subunit of replication protein A, which carries most of the ssDNA-binding folds and the N-terminal fold that hands the lesion to ATR

No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.

• RPA is required in every dividing cell, so any RPA-directed intervention has a therapeutic-window problem that no interactome or occupancy result speaks to. RPA inhibitors targeting the ssDNA-binding and protein-interaction surfaces exist in the literature, which makes this more urgent, not less.
• The ATR axis downstream of RPA is the druggable end of this pathway and ATR/ATM inhibition already shows antitumour activity in MLL-rearranged AML mouse models (PMID 27625305). But RPA exhaustion is the mechanism by which ATR inhibition kills (PMID 24267891), so an RPA-directed and an ATR-directed agent are not additive in the naive sense: lowering RPA accelerates fork breakage, which is the same lever pulled twice.
• If the menin-RPA2 contact operates in this disease, a menin inhibitor could displace RPA2 from menin as a side effect, and the direction of that effect on HR is unknown - protective (freeing RPA2) or harmful (removing a scaffold). Nobody has measured it, and the corpus's existing HR-competence experiment under menin inhibition does not read out RPA.

1. Is RPA1 or RPA3 detected at all in PXD009338 below the published top-300-per-bait cut? The Q180 decline of RPA2 rests partly on their absence and the raw deposit can answer it with no wet work. That is exp-q180-reanalyse-pxd009338-for-peptide-level-evidence-under-the-rank-cut, and it has not been run.
2. Does a menin antibody co-precipitate RPA1 from a KMT2A-rearranged blast, as it does from HeLa (PMID 12509449)? That single co-IP would move the menin-RPA contact from an endocrine-tumour literature into this disease.
3. ETAA1 has no entry in this corpus and is the RPA-binding ATR activator running parallel to the ATRIP route. Is it expressed and required in KMT2A-rearranged blasts? If the ATR dependence reported for MLL-rearranged AML (PMID 27625305) runs through ETAA1 rather than ATRIP, the RPA-side target is a different protein.
4. What are the human DBD-A, DBD-B, DBD-C and DBD-F residue boundaries against P27694, confirmed from a human structure? This entry deliberately records none, because the most-cited full-trimer structure is a fungal protein.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   RPA1 is UniProt P27694 (RFA1_HUMAN), primary gene symbol RPA1, 616 aa, 'Replication protein A 70 kDa DNA-binding subunit', with an OB fold at 197-281 and a C4-type zinc finger at 481-503, annotated to Nucleus (ECO:0000269 PubMed 17596542, 17959650) and to nuclear PML body (ECO:0000269 PubMed 17959650), and described as a component of the canonical RPA heterotrimer composed of RPA1, RPA2 and RPA3.

   UniProtKB P27694 (RFA1_HUMAN), Replication protein A 70 kDa DNA-binding subunit - accession, primary gene name, sequence length, feature table and subcellular-location and subunit comments, fetched live 2026-09-24 · UniProt Consortium, EMBL-EBI/SIB/PIR 2026
   ▸What this evidence cannot show

   Resolved by accession with the primary gene name read back, and the sequence MD5 recorded (EFF7F8FCF3AFB217E6B2BCE37F5CB6CB) so a later reader can tell whether the record changed. Rule 91 applies: the two ECO:0000269 localisation citations mean a curator saw experiments in those papers, not that either is the founding or best localisation study; neither was opened for this entry. Rule 93 applies to the symbol: RPA1 is ALSO a curated HGNC alias of POLR1A (HGNC:17264, RNA polymerase I subunit A), so an alias-expanded database lookup on 'RPA1' returns the wrong protein - see ana-q192-rpa1-and-rpa2-are-hgnc-curated-aliases-of-rna-polymerase-i-subunits. UniProt annotates only ONE OB fold although the DBD-A/B/C/F nomenclature in the structural literature implies several; the four-domain description is drawn from the structural literature [E7] and the two vocabularies must not be mixed.

   ▸Evidence that argues against this (1)

   • A UniProt subunit record is not evidence that the subunit matters in this disease, and this entry should not be read as asserting that it does. RPA1 has no published connection to any KMT2A fusion and is absent from the only MLL-fusion AP-MS network that exists, under all seven baits. The accession and the feature table are correct and are also the least informative part of this beat. Nature Communications 2018
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   Human Protein Atlas immunofluorescence localises RPA1 to Nucleoplasm with reliability 'Supported', and the same query returns POLR1A carrying RPA1 as a gene synonym with a different localisation (Nucleoplasm, Nucleoli fibrillar center, Cytosol).

   Human Protein Atlas search_download API, query 'RPA1', columns gene/ensembl/synonym/subcellular-location/reliability, fetched 2026-09-24; RPA1 = ENSG00000132383, Reliability (IH) Supported, Subcellular location [Nucleoplasm] · Human Protein Atlas, proteinatlas.org 2026
   ▸What this evidence cannot show

   HPA immunofluorescence is antibody-based in fixed cultured cell lines, not a haematopoietic cell, and 'Supported' is HPA's middle reliability tier, not 'Enhanced'. Rule 74 applies: the antibody identifier, not the label, is what a reader needs, and this column set does not return it. The Ensembl id ENSG00000132383 came from the same response as the symbol and was NOT independently resolved - it is recorded as HPA's own join, not as a verified gene identity, because this project has already had an Ensembl id resolve to the wrong gene.

   ▸Evidence that argues against this (1)

   • An immunofluorescence compartment call cannot distinguish free RPA1 from the heterotrimer, and for RPA those are the biologically distinct species - the menin literature turns on exactly that distinction [E5]. So 'Nucleoplasm, Supported' is consistent with every model of RPA1 behaviour and discriminates between none of them. Searched for a paper disputing RPA1's nuclear residence and found none: the compartment is not in doubt, the resolution is. UniProt Consortium 2026
3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   RPA is required for the recruitment of ATR to sites of DNA damage and for ATR-mediated Chk1 activation in human cells; RPA stimulates the binding of ATRIP to ssDNA in vitro, and the checkpoint-deficient RPA mutant rfa1-t11 - an allele of the RPA large subunit - is defective for recruiting the budding-yeast ATRIP homologue Ddc2 to ssDNA both in vivo and in vitro.

   Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. · Zou L, Elledge SJ · Science 300(5625):1542-8 2003
   PMID 12791985DOI
   ▸What this evidence cannot show

   Read at abstract level via PubMed efetch; the full text was not opened. HeLa cells plus purified proteins plus budding yeast. The genetic evidence pinning the requirement to the large subunit is the SACCHAROMYCES rfa1-t11 allele, so that residue is a yeast coordinate and must not be mapped onto human RPA1 numbering; this item therefore quotes no human residue. No haematopoietic cell and no fusion-oncoprotein context appears in this paper.

   ▸Evidence that argues against this (1)

   • This is the canonical model and the corpus should hold where it is known to be incomplete: ATR can also be activated through TOPBP1- and ETAA1-dependent routes, and ETAA1 binds RPA directly but activates ATR by a mechanism distinct from the ATRIP route. The corpus carries gene-topbp1, so one alternative activator is written down; ETAA1 has NO entry anywhere here and is a named gap this beat leaves open. UniProt Consortium 2026
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   No paper names RPA1 together with MLL in a title or abstract, and the two that name RPA1 with KMT2A are both off-topic: a review of the quassinoid Ailanthone (J Ethnopharmacol 2025, PMID 41083063) and a three-case series of pulmonary granular cell tumour (Transl Cancer Res 2020, PMID 35117846).

   PubMed esearch via scripts/pubmed_safe.py, run 2026-09-24 by Q192. RPA1[tiab] AND MLL[tiab] -> 0, querytranslation "RPA1"[Title/Abstract] AND "MLL"[Title/Abstract], genuine zero. RPA1[tiab] AND KMT2A[tiab] -> 2, querytranslation "RPA1"[Title/Abstract] AND "KMT2A"[Title/Abstract], ids 41083063 and 35117846, both title-checked by efetch and both off-topic. · NCBI PubMed E-utilities 2026
   ▸What this evidence cannot show

   Bounded by titles and abstracts (rule 80): an RPA1 blot in a supplementary figure of a KMT2A paper is invisible to this query, and for a repair protein that is where such a measurement would sit. One tag per term (rule 94) and both querytranslations read back. RPA-side name list tried: RPA1, RPA70, 'replication protein A', 'RPA complex'. NOT tried: REPA1, HSSB, RF-A, RP-A. Fusion-side list tried: MLL, KMT2A only.

   ▸Evidence that argues against this (1)

   • This zero is NOT an absence of RPA at the KMT2A locus, and reading it that way is the mistake this beat found and corrected. RPA occupancy at the MLL/KMT2A breakpoint cluster region after etoposide IS published, by ChIP at the 11q23 breakpoint hotspot, and it is invisible to any subunit-symbol query because the paper writes 'Replication protein A (RPA)' and never the subunit symbol. The complex-name query found it and the symbol queries did not, which is rule 64 firing in real time. Sun J et al. 2010
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Menin binds preferentially in vitro to free RPA2 rather than to the RPA heterotrimer or to an RPA2-RPA3 subcomplex, but RPA1 was co-precipitated from HeLa cell extracts along with RPA2 by menin-specific antibodies, suggesting menin engages the heterotrimer or a novel RPA1-RPA2-containing complex in vivo, consistent with extensive overlap of the nuclear localisation patterns of endogenous menin, RPA2 and RPA1 by immunofluorescence.

   The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene. · Sukhodolets KE, Hickman AB, Agarwal SK, Sukhodolets MV, Obungu VH, Novotny EA, Crabtree JS, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ · Molecular and Cellular Biology 23(2):493-509 2003
   PMID 12509449DOI
   ▸What this evidence cannot show

   Abstract plus a targeted read of the PMC full text for the mapping and mutation data; the figures were not inspected. The in-vitro preference and the in-cell co-precipitation point in OPPOSITE directions and the authors say so - the paper does not resolve which species menin binds in a cell. HeLa, not a haematopoietic cell, and no KMT2A-rearranged system appears anywhere in the paper. A co-precipitation with a menin antibody cannot distinguish a menin-RPA1 contact from RPA1 riding along on RPA2. 2003, before menin's structure was solved.

   ▸Evidence that argues against this (1)

   • The same paper reports the negative that most constrains any model built on it: menin showed NO detectable mobilisation into replication foci, and when cells were synchronised at the G1/S border so that punctate RPA2 prereplication foci were visible, menin's localisation appeared similar to untreated cells. Whatever the menin-RPA2 contact is, the paper's own imaging argues it is not a replication-fork event - which removes the mechanism a reader would reach for first. Sukhodolets KE et al. 2003
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Menin directly recognises gamma-H2A.X via a Val371-Gln400 motif and recruits SETD2 to damage sites, where H3K36me3 is read by LEDGF, which recruits CtIP as an effector to perform DNA end resection, ultimately activating the RPA2/Rad51 pathway; restoring H3K36me3 pharmacologically rescued impaired homologous recombination in Men1-deficient cells.

   The tumor suppressor menin is a key scaffold mediator for homologous recombination repair. · Lian A, Zhu X, Jin B, Gu G, Xu B, Zhang L, Lin X, Zhu X, Jin G · Nucleic Acids Research 54(15) 2026
   PMID 42578372DOI
   ▸What this evidence cannot show

   Abstract level here. This paper is already cited 19 times in this corpus and the entries carrying its full treatment are hyp-the-menin-arm-and-the-ctcf-arm-license-consecutive-steps-of-one-resection-reaction, gene-rbbp8, ana-q34-menin-surface-geometry and exp-hr-competence-under-menin-inhibition-in-kmt2a-rearranged-blasts - read those, not this item, for the mechanism. Mouse Men1 ablation with lung carcinogenesis as the in-vivo system; no haematopoietic and no KMT2A-rearranged arm. 'The RPA2/Rad51 pathway' is named as the terminal step and is not measured at subunit resolution in the abstract, which is why this item is graded moderate for the RPA2 claim specifically rather than for the paper.

   ▸Evidence that argues against this (1)

   • This is a menin-LOSS axis and the index disease is a menin-DEPENDENCE axis - the opposite perturbation. A KMT2A fusion does not lose menin, it recruits it. So an HR defect in Men1-null cells does not predict an HR defect in a KMT2A-rearranged cell, and predicts one under a menin INHIBITOR only if the inhibitor disrupts this scaffold function, which the corpus has already flagged is not established because the gamma-H2A.X-binding Val371-Gln400 motif is not the KMT2A-binding pocket revumenib occupies. This repository 2026
7. E7established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   Human RPA binds ssDNA in at least two modes, an initial 8-10 nucleotide mode and a stable approximately 30 nucleotide mode, and the switch between them is mediated by DNA binding with the trimerisation core; the 2.8 Angstrom structure of that core comprises the C-terminal DNA-binding domain of RPA70 (DBD-C), the central DNA-binding domain of RPA32 (DBD-D) and the entire RPA14 subunit, each built around a central OB fold flanked by a C-terminal helix, with trimerisation mediated by three parallel C-terminal helices, and DBD-C carrying an embedded zinc ribbon and helix-turn-helix.

   Structure of the RPA trimerization core and its role in the multistep DNA-binding mechanism of RPA. · Bochkareva E, Korolev S, Lees-Miller SP, Bochkarev A · EMBO Journal 21(7):1855-63 2002
   PMID 11927569DOI
   ▸What this evidence cannot show

   Abstract level. HUMAN protein, which is why this and not the later full-trimer structure is used as the architectural reference: the 2012 full-length RPA-ssDNA structure (PMID 23070815) is a USTILAGO MAYDIS heterotrimer (MeSH 'Fungal Proteins', 'Ustilago') and its residue numbering does not transfer to human RPA. The zinc-ribbon location is consistent with UniProt's C4-type zinc finger at P27694 residues 481-503 [E1], which is the only cross-check performed; no PDB coordinate file was downloaded and no residue range from this paper is quoted here.

   ▸Evidence that argues against this (1)

   • The two-mode model describes purified protein on naked oligonucleotides, and the 8-10 and ~30 nt figures are occluded-site sizes from time-resolved proteolysis, not measurements in a cell. In chromatin, RPA's footprint and residence time are set by competing ssDNA-binding proteins and by RPA2 phosphorylation, none of which this structure addresses. Searched for a paper disputing the two-mode model and found none - the model is not contested; its transferability to a nucleus is. Fan J et al. 2012

• part of →The replication protein A heterotrimer (RPA1/RPA2/RPA3) - the ssDNA clamp that every resection and replication-stress claim in this corpus silently depends on, and which had no entry until cycle 160

  70 kDa subunit; contributes DBD-C to the trimerisation core

• binds →RPA2 (RPA32) - the middle subunit of replication protein A, whose disordered N-terminus is the phospho-switch of the replication-stress response and whose 43-171 region binds menin

  heterotrimer partners; menin antibodies co-precipitate both from HeLa

• ← related toRPA1 and RPA2 are curated HGNC aliases of POLR1A and POLR1B, and RPA34 - a UniProt synonym of RPA2 - is an alias of POLR1G, so three of the ssDNA clamp's names point at RNA polymerase I subunits; the hazard is in symbol-based DATABASE lookups, not in PubMed, and the measured contamination says which

  symbol-collision record for RPA1 / POLR1A