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Gene Review

RPA1  -  replication protein A1, 70kDa

Homo sapiens

Synonyms: HSSB, MST075, REPA1, RF-A, RF-A protein 1, ...
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Disease relevance of RPA1


High impact information on RPA1


Chemical compound and disease context of RPA1


Biological context of RPA1

  • Cells lacking RPA1 accumulate as multiply budded cells with a single nucleus suggesting a defect in DNA replication [13].
  • RNA interference-mediated suppression of RPA1 caused a slowing of S phase progression, G2/M cell cycle arrest, and apoptosis in HeLa cells [14].
  • Differential expression during the life cycle stages in three apicomplexan parasites suggests that the two RPA1 types exercise specialized biological functions [15].
  • Apicomplexan RPA1 proteins are phylogenetically more related to plant homologues and probably arose from a single gene duplication event prior to the expansion of the apicomplexan lineage [15].
  • The phosphorylation status of the p34 subunit of HSSB was unchanged during the reactions [1].

Anatomical context of RPA1

  • Replication factor A (RPA) is a protein that binds single-stranded DNA in eukaryotic cells; it participates in replication, repair, and recombination of DNA [16].
  • In human umbilical vein endothelial cells, inhibition of RPA1 expression using antisense oligonucleotide restored transcription driven by the mutated promoter sequence, whereas, conversely, overexpression of RPA1 further reduced it [17].
  • RPA1 thus apparently functions as a repressor protein in the -786T-->C mutation-related reduction of eNOS gene transcription associated with the development of coronary artery disease [17].
  • RPA1 was similarly detected in placenta and eNOS mRNA levels in placentas carrying the -786T-->C mutation were significantly lower than in placentas without it [17].
  • These results demonstrate that in HL-60 cells, Hoechst 33342-induced apoptosis is associated with a rapid loss of the binding capacity of RPA to oligo(dT)(30) as well as immunoactive RPA-70 and RPA-32 [18].

Associations of RPA1 with chemical compounds


Physical interactions of RPA1


Enzymatic interactions of RPA1

  • Both Cdc2 kinase and the DNA-dependent protein kinase (DNA-PK) phosphorylate HSSB-p34 in vitro [28].
  • While ATR phosphorylates the N-terminus of RPA70, Chk1 preferentially phosphorylates RPA's major ssDNA binding domain [29].

Co-localisations of RPA1


Regulatory relationships of RPA1

  • Fractionation of cyclin A-activated G1 extract identified two kinases involved in the hyperphosphorylation of HSSB p34: cdk-cyclin A complex and DNA-dependent p350 protein kinase (DNA-PK) [31].
  • The stimulatory effect of HSSB was markedly inhibited by the combined action of A1 and PCNA [32].
  • The 3'-5' exonuclease activity was stimulated 8-10 fold by the addition of HSSB, and this stimulatory effect was preferential to HSSB since other SSBs from E. coli, T4 or adenovirus, had a little or no effect [32].
  • The N-terminal 168 residues of RPA70 form a structurally distinct domain that stimulates DNA polymerase alpha activity, interacts with several transcriptional activators including tumor suppressor p53, and during the cell cycle it signals escape from the DNA damage induced G2/M checkpoint [33].
  • Both wild-type p53 and a transactivation-deficient p53 mutant (L22Q/W23S) suppressed HR and prevented RPA binding to ssDNA in vitro and in vivo [34].

Other interactions of RPA1

  • In this study, we investigated the effect of phosphorylation of p34 by these kinases on the replication and repair function of HSSB [1].
  • Addition of p21cip1, a specific inhibitor of cdk-cyclin A but not DNA-PK, nearly abolished the hyperphosphorylation of HSSB p34 in G1 extract preincubated with cyclin A. This suggests a requirement of the cdk-cyclin A activity for the phosphorylation of p34 by DNA-PK in G1 extract [31].
  • Here, we demonstrate that the ATR checkpoint kinase and RPA1 are required for efficient FANCD2 monoubiquitination [35].
  • We examined the effect of this XPAC-RPA interaction on in vitro simian virus 40 (SV40) DNA replication catalyzed by the monopolymerase system [27].
  • In addition, the consistent formation of phospho-Nbs1 foci in all of the treatment groups suggests that the MRN complex may play a more universal role in the recognition and response to DNA lesions of all types, whereas the role of RPA may be limited to certain subsets of lesions [36].

Analytical, diagnostic and therapeutic context of RPA1

  • Gel filtration analyses of cellular extracts showed that endogenous (HSA)kin17 protein co-eluted with both replication proteins RPA32 and RPA70 in a fraction containing complexes of M(r) 600,000 [37].
  • Using a gel retardation assay, we show here that nuclear extracts of C. fasciculata contain a protein factor(s) that binds specifically to RNA from 5'-UTRs of TOP2 and RPA1 genes [38].
  • We report here that, by using affinity chromatography and immunoprecipitation, we found that human RPA bound specifically and directly to two excision repair proteins, the xeroderma pigmentosum damage-recognition protein XPA (refs 8, 9) and the endonuclease XPG (refs 10-13) [39].
  • Thus, one fraction carries out nick-directed and mismatch-dependent excision; the second carries out DNA repair synthesis and DNA ligation; and the third provides hRPA, which plays multiple roles in human MMR by protecting the template DNA strand from degradation, enhancing repair excision, and facilitating repair synthesis [40].
  • In vitro dissection of the MMR reaction and crucial intermediates elucidated biochemical functions of individual fractions in human MMR and identified hitherto unknown functions of human replication protein A (hRPA) in MMR [40].


  1. Phosphorylated and unphosphorylated forms of human single-stranded DNA-binding protein are equally active in simian virus 40 DNA replication and in nucleotide excision repair. Pan, Z.Q., Park, C.H., Amin, A.A., Hurwitz, J., Sancar, A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  2. Genetic analysis of yeast RPA1 reveals its multiple functions in DNA metabolism. Umezu, K., Sugawara, N., Chen, C., Haber, J.E., Kolodner, R.D. Genetics (1998) [Pubmed]
  3. Reconstitution of functional human single-stranded DNA-binding protein from individual subunits expressed by recombinant baculoviruses. Stigger, E., Dean, F.B., Hurwitz, J., Lee, S.H. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  4. DNA unwinding by replication protein A is a property of the 70 kDa subunit and is facilitated by phosphorylation of the 32 kDa subunit. Georgaki, A., Hübscher, U. Nucleic Acids Res. (1993) [Pubmed]
  5. Autoantibodies against the replication protein A complex in systemic lupus erythematosus and other autoimmune diseases. Yamasaki, Y., Narain, S., Hernandez, L., Barker, T., Ikeda, K., Segal, M.S., Richards, H.B., Chan, E.K., Reeves, W.H., Satoh, M. Arthritis Res. Ther. (2006) [Pubmed]
  6. Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Wold, M.S. Annu. Rev. Biochem. (1997) [Pubmed]
  7. An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Maser, R.S., Zinkel, R., Petrini, J.H. Nat. Genet. (2001) [Pubmed]
  8. Replication focus-forming activity 1 and the Werner syndrome gene product. Yan, H., Chen, C.Y., Kobayashi, R., Newport, J. Nat. Genet. (1998) [Pubmed]
  9. Inhibition of the defense system stimulating interleukin-12 interferon-gamma pathway during critical Illness. Ertel, W., Keel, M., Neidhardt, R., Steckholzer, U., Kremer, J.P., Ungethuem, U., Trentz, O. Blood (1997) [Pubmed]
  10. p10, a low molecular weight single-stranded nucleic acid binding protein of murine leukemia retroviruses, shows stacking interactions of its single tryptophan residue with nucleotide bases. Casas-Finet, J.R., Jhon, N.I., Maki, A.H. Biochemistry (1988) [Pubmed]
  11. Surface display of an internal His-tag on virus-like particles of Nudaurelia capensis omega virus (NomegaV) produced in a baculovirus expression system. Maree, H.J., van der Walt, E., Tiedt, F.A., Hanzlik, T.N., Appel, M. J. Virol. Methods (2006) [Pubmed]
  12. Expression of a leukemia-associated antigen (CAMAL) in four myeloid leukemia cell lines. Shipman, R.C., Levy, J.G. Leuk. Res. (1988) [Pubmed]
  13. An essential Saccharomyces cerevisiae single-stranded DNA binding protein is homologous to the large subunit of human RP-A. Heyer, W.D., Rao, M.R., Erdile, L.F., Kelly, T.J., Kolodner, R.D. EMBO J. (1990) [Pubmed]
  14. DNA replication defects, spontaneous DNA damage, and ATM-dependent checkpoint activation in replication protein A-deficient cells. Dodson, G.E., Shi, Y., Tibbetts, R.S. J. Biol. Chem. (2004) [Pubmed]
  15. The protozoan parasite Cryptosporidium parvum possesses two functionally and evolutionarily divergent replication protein A large subunits. Rider, S.D., Cai, X., Sullivan, W.J., Smith, A.T., Radke, J., White, M., Zhu, G. J. Biol. Chem. (2005) [Pubmed]
  16. Study of interaction of human replication factor A with DNA using new photoreactive analogs of dTTP. Kolpashchikov, D.M., Pestryakov, P.E., Wlassoff, W.A., Khodyreva, S.N., Lavrik, O.I. Biochemistry Mosc. (2000) [Pubmed]
  17. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T-->C mutation associated with coronary spastic angina. Miyamoto, Y., Saito, Y., Nakayama, M., Shimasaki, Y., Yoshimura, T., Yoshimura, M., Harada, M., Kajiyama, N., Kishimoto, I., Kuwahara, K., Hino, J., Ogawa, E., Hamanaka, I., Kamitani, S., Takahashi, N., Kawakami, R., Kangawa, K., Yasue, H., Nakao, K. Hum. Mol. Genet. (2000) [Pubmed]
  18. Disruption of replication protein A/single-stranded DNA complexes during apoptosis in HL-60 cells. Zhang, X., Kiechle, F.L. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  19. Replication protein A and the Mre11.Rad50.Nbs1 complex co-localize and interact at sites of stalled replication forks. Robison, J.G., Elliott, J., Dixon, K., Oakley, G.G. J. Biol. Chem. (2004) [Pubmed]
  20. The role for zinc in replication protein A. Bochkareva, E., Korolev, S., Bochkarev, A. J. Biol. Chem. (2000) [Pubmed]
  21. Cloning of the large subunit of replication protein A (RPA) from yeast Saccharomyces cerevisiae and its DNA binding activity through redox potential. Jeong, H.S., Jeong, I.C., Kim, A., Kang, S.W., Kang, H.S., Kim, Y.J., Lee, S.H., Park, J.S. J. Biochem. Mol. Biol. (2002) [Pubmed]
  22. Loss of RPA1 induces Chk2 phosphorylation through a caffeine-sensitive pathway. Araya, R., Hirai, I., Meyerkord, C.L., Wang, H.G. FEBS Lett. (2005) [Pubmed]
  23. Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes. Shao, R.G., Cao, C.X., Zhang, H., Kohn, K.W., Wold, M.S., Pommier, Y. EMBO J. (1999) [Pubmed]
  24. Coordinated regulation of replication protein A activities by its subunits p14 and p32. Weisshart, K., Pestryakov, P., Smith, R.W., Hartmann, H., Kremmer, E., Lavrik, O., Nasheuer, H.P. J. Biol. Chem. (2004) [Pubmed]
  25. The RPA32 subunit of human replication protein A contains a single-stranded DNA-binding domain. Bochkareva, E., Frappier, L., Edwards, A.M., Bochkarev, A. J. Biol. Chem. (1998) [Pubmed]
  26. Analysis of the human replication protein A:Rad52 complex: evidence for crosstalk between RPA32, RPA70, Rad52 and DNA. Jackson, D., Dhar, K., Wahl, J.K., Wold, M.S., Borgstahl, G.E. J. Mol. Biol. (2002) [Pubmed]
  27. Human xeroderma pigmentosum group A protein interacts with human replication protein A and inhibits DNA replication. Lee, S.H., Kim, D.K., Drissi, R. J. Biol. Chem. (1995) [Pubmed]
  28. Mapping of amino acid residues in the p34 subunit of human single-stranded DNA-binding protein phosphorylated by DNA-dependent protein kinase and Cdc2 kinase in vitro. Niu, H., Erdjument-Bromage, H., Pan, Z.Q., Lee, S.H., Tempst, P., Hurwitz, J. J. Biol. Chem. (1997) [Pubmed]
  29. Phosphorylation of replication protein A by S-phase checkpoint kinases. Liu, J.S., Kuo, S.R., Melendy, T. DNA Repair (Amst.) (2006) [Pubmed]
  30. Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest. Constantinou, A., Tarsounas, M., Karow, J.K., Brosh, R.M., Bohr, V.A., Hickson, I.D., West, S.C. EMBO Rep. (2000) [Pubmed]
  31. Phosphorylation of the p34 subunit of human single-stranded-DNA-binding protein in cyclin A-activated G1 extracts is catalyzed by cdk-cyclin A complex and DNA-dependent protein kinase. Pan, Z.Q., Amin, A.A., Gibbs, E., Niu, H., Hurwitz, J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  32. The 3'-5' exonuclease of human DNA polymerase delta (pol delta) is regulated by pol delta accessory factors and deoxyribonucleoside triphosphates. Lee, S.H. Nucleic Acids Res. (1993) [Pubmed]
  33. Human replication protein A: global fold of the N-terminal RPA-70 domain reveals a basic cleft and flexible C-terminal linker. Jacobs, D.M., Lipton, A.S., Isern, N.G., Daughdrill, G.W., Lowry, D.F., Gomes, X., Wold, M.S. J. Biomol. NMR (1999) [Pubmed]
  34. The interaction of p53 with replication protein A mediates suppression of homologous recombination. Romanova, L.Y., Willers, H., Blagosklonny, M.V., Powell, S.N. Oncogene (2004) [Pubmed]
  35. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Andreassen, P.R., D'Andrea, A.D., Taniguchi, T. Genes Dev. (2004) [Pubmed]
  36. DNA lesion-specific co-localization of the Mre11/Rad50/Nbs1 (MRN) complex and replication protein A (RPA) to repair foci. Robison, J.G., Lu, L., Dixon, K., Bissler, J.J. J. Biol. Chem. (2005) [Pubmed]
  37. Participation of kin17 protein in replication factories and in other DNA transactions mediated by high molecular weight nuclear complexes. Biard, D.S., Miccoli, L., Despras, E., Harper, F., Pichard, E., Créminon, C., Angulo, J.F. Mol. Cancer Res. (2003) [Pubmed]
  38. Nuleclear extracts of Crithidia fasciculata contain a factor(s) that binds to the 5'-untranslated regions of TOP2 and RPA1 mRNAs containing sequences required for their cell cycle regulation. Mahmood, R., Ray, D.S. J. Biol. Chem. (1998) [Pubmed]
  39. RPA involvement in the damage-recognition and incision steps of nucleotide excision repair. He, Z., Henricksen, L.A., Wold, M.S., Ingles, C.J. Nature (1995) [Pubmed]
  40. Partial reconstitution of human DNA mismatch repair in vitro: characterization of the role of human replication protein A. Ramilo, C., Gu, L., Guo, S., Zhang, X., Patrick, S.M., Turchi, J.J., Li, G.M. Mol. Cell. Biol. (2002) [Pubmed]
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