Genomes and Genes
Gene Symbol: RPA1
Description: replication protein A1
Alias: HSSB, MST075, REPA1, RF-A, RP-A, RPA70, replication protein A 70 kDa DNA-binding subunit, MSTP075, RF-A protein 1, RP-A p70, replication factor A protein 1, replication protein A1, 70kDa, single-stranded DNA-binding protein
- Shuck S, Turchi J. Targeted inhibition of Replication Protein A reveals cytotoxic activity, synergy with chemotherapeutic DNA-damaging agents, and insight into cellular function. Cancer Res. 2010;70:3189-98 pubmed publisher..This represents the first molecularly targeted eukaryotic DNA-binding inhibitor and reveals the utility of targeting a protein-DNA interaction as a therapeutic strategy for cancer treatment. ..
- Derheimer F, O Hagan H, Krueger H, Hanasoge S, Paulsen M, Ljungman M. RPA and ATR link transcriptional stress to p53. Proc Natl Acad Sci U S A. 2007;104:12778-83 pubmed..We propose that this transcription-based stress response involving RPA, ATR, and p53 has evolved as a DNA damage-sensing mechanism to safeguard cells against DNA damage-induced mutagenesis. ..
- Haring S, Mason A, Binz S, Wold M. Cellular functions of human RPA1. Multiple roles of domains in replication, repair, and checkpoints. J Biol Chem. 2008;283:19095-111 pubmed publisher..RPA is composed of the following three subunits: RPA1, RPA2, and RPA3...
- Oakley G, Patrick S. Replication protein A: directing traffic at the intersection of replication and repair. Front Biosci (Landmark Ed). 2010;15:883-900 pubmed..This review summarizes the current understanding of RPA structure, phosphorylation and protein-protein interactions in mediating these DNA metabolic processes. ..
- Pretto D, Tsutakawa S, Brosey C, Castillo A, Chagot M, Smith J, et al. Structural dynamics and single-stranded DNA binding activity of the three N-terminal domains of the large subunit of replication protein A from small angle X-ray scattering. Biochemistry. 2010;49:2880-9 pubmed publisher..X-ray scattering (SAXS) experiments with two multidomain constructs from the N-terminus of the large subunit (RPA70) were used to examine the structural dynamics of these domains and their response to the binding of ssDNA...
- Bastin Shanower S, Brill S. Functional analysis of the four DNA binding domains of replication protein A. The role of RPA2 in ssDNA binding. J Biol Chem. 2001;276:36446-53 pubmed..ssDNA)-binding protein of eukaryotes, contains four ssDNA binding domains (DBDs) within its two largest subunits, RPA1 and RPA2...
- Machida Y, Kim M, Machida Y. Spartan/C1orf124 is important to prevent UV-induced mutagenesis. Cell Cycle. 2012;11:3395-402 pubmed publisher..Taken together, our data suggest that Spartan is recruited to sites of stalled replication via ubiquitinated PCNA and plays an important role to prevent mutations associated with replication of damaged DNA. ..
- Anantha R, Sokolova E, Borowiec J. RPA phosphorylation facilitates mitotic exit in response to mitotic DNA damage. Proc Natl Acad Sci U S A. 2008;105:12903-8 pubmed publisher..Our results demonstrate that mitotic RPA hyperphosphorylation facilitates release of cells from a damaged mitosis into a 2N G(1) phase, thereby increasing cell viability. ..
- Jackson D, Dhar K, Wahl J, Wold M, Borgstahl G. Analysis of the human replication protein A:Rad52 complex: evidence for crosstalk between RPA32, RPA70, Rad52 and DNA. J Mol Biol. 2002;321:133-48 pubmed..C-terminal domain (CTD) of RPA32 (residues 224-271) and the newly identified domain containing residues 169-326 of RPA70. A region on Rad52, which includes residues 218-303, binds RPA70 as well as RPA32...
- Grudic A, Jul Larsen A, Haring S, Wold M, Lønning P, Bjerkvig R, et al. Replication protein A prevents accumulation of single-stranded telomeric DNA in cells that use alternative lengthening of telomeres. Nucleic Acids Res. 2007;35:7267-78 pubmed..This study demonstrates differences between ALT cells and telomerase-positive cells in the requirement for RPA in telomere processing and implicates the ALT mechanism in tumor cells as a possible therapeutic target. ..
- Wyka I, Dhar K, Binz S, Wold M. Replication protein A interactions with DNA: differential binding of the core domains and analysis of the DNA interaction surface. Biochemistry. 2003;42:12909-18 pubmed..Our data are consistent with a sequential binding model for RPA, in which DBD A is responsible for positioning and initial binding of the RPA complex while DBD A together with DBD B direct stable, high-affinity binding to ssDNA. ..
- Shao R, Cao C, Zhang H, Kohn K, Wold M, Pommier Y. Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes. EMBO J. 1999;18:1397-406 pubmed..DNA-PKcs interacted directly with RPA1 in vitro...
- Zou L, Liu D, Elledge S. Replication protein A-mediated recruitment and activation of Rad17 complexes. Proc Natl Acad Sci U S A. 2003;100:13827-32 pubmed..These results explain how the Rad17-Rfc2-5 complex senses DNA damage and DNA replication stress to initiate checkpoint signaling. ..
- Hass C, Gakhar L, Wold M. Functional characterization of a cancer causing mutation in human replication protein A. Mol Cancer Res. 2010;8:1017-26 pubmed publisher..To understand the molecular defect causing these phenotypes, we created the homologous mutation in the human RPA1 gene (L221P) and analyzed its properties in cells and in vitro...
- Brosh R, Li J, Kenny M, Karow J, Cooper M, Kureekattil R, et al. Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity. J Biol Chem. 2000;275:23500-8 pubmed..The interactions between BLM and hRPA suggest that the two proteins function together in vivo to unwind DNA duplexes during replication, recombination, or repair. ..
- Shen J, Lao Y, Kamath Loeb A, Wold M, Loeb L. The N-terminal domain of the large subunit of human replication protein A binds to Werner syndrome protein and stimulates helicase activity. Mech Ageing Dev. 2003;124:921-30 pubmed..These data should help further elucidation of the molecular mechanisms of genetic instability and premature aging phenotypes manifested by WS. ..
- Bochkareva E, Korolev S, Lees Miller S, Bochkarev A. Structure of the RPA trimerization core and its role in the multistep DNA-binding mechanism of RPA. EMBO J. 2002;21:1855-63 pubmed..8 A structure of the RPA trimerization core comprising the C-terminal DNA-binding domain of subunit RPA70 (DBD-C), the central DNA-binding domain of subunit RPA32 (DBD-D) and the entire RPA14 subunit...
- Cai L, Roginskaya M, Qu Y, Yang Z, Xu Y, Zou Y. Structural characterization of human RPA sequential binding to single-stranded DNA using ssDNA as a molecular ruler. Biochemistry. 2007;46:8226-33 pubmedHuman replication protein A (RPA), a heterotrimer composed of RPA70, RPA32, and RPA14 subunits, contains four single-stranded DNA (ssDNA) binding domains (DBD): DBD-A, DBD-B, and DBD-C in RPA70 and DBD-D in RPA32...
- Sommers J, Sharma S, Doherty K, Karmakar P, Yang Q, Kenny M, et al. p53 modulates RPA-dependent and RPA-independent WRN helicase activity. Cancer Res. 2005;65:1223-33 pubmed..Regulation of WRN helicase activity by p53 is likely to play an important role in genomic integrity surveillance, a vital function in the prevention of tumor progression. ..
- DeMott M, Zigman S, Bambara R. Replication protein A stimulates long patch DNA base excision repair. J Biol Chem. 1998;273:27492-8 pubmed..It also has been shown to interact with an early component of base excision repair: uracil glycosylase. Here we show that human replication protein A greatly stimulates long patch base excision repair. ..
- Sugiyama T, Kowalczykowski S. Rad52 protein associates with replication protein A (RPA)-single-stranded DNA to accelerate Rad51-mediated displacement of RPA and presynaptic complex formation. J Biol Chem. 2002;277:31663-72 pubmed..This acceleration probably involves direct interactions with both Rad51 protein and RPA. Detection of a Rad52-RPA-ssDNA co-complex suggests that this co-complex is an intermediate in the displacement process. ..
- Deng X, Prakash A, Dhar K, Baia G, Kolar C, Oakley G, et al. Human replication protein A-Rad52-single-stranded DNA complex: stoichiometry and evidence for strand transfer regulation by phosphorylation. Biochemistry. 2009;48:6633-43 pubmed publisher..This suggests that RPA phosphorylation may regulate the first steps of DSB repair and is necessary for the mediator function of Rad52. ..
- Cardoso C, Leventer R, Ward H, Toyo oka K, Chung J, Gross A, et al. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet. 2003;72:918-30 pubmed
- Chaudhuri J, Khuong C, Alt F. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature. 2004;430:992-8 pubmed..We propose that B-cell-specific AID-RPA complexes preferentially bind to ssDNA of small transcription bubbles at SHM 'hotspots', leading to AID-mediated deamination and RPA-mediated recruitment of DNA repair proteins. ..
- Opresko P, Von Kobbe C, Laine J, Harrigan J, Hickson I, Bohr V. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J Biol Chem. 2002;277:41110-9 pubmed..These results suggest that TRF2 functions with WRN, and possibly BLM, in a common pathway at telomeric ends. ..
- Wu X, Shell S, Zou Y. Interaction and colocalization of Rad9/Rad1/Hus1 checkpoint complex with replication protein A in human cells. Oncogene. 2005;24:4728-35 pubmed..A (RPA) is a eukaryotic single-stranded DNA-binding protein consisting of three subunits of 70-, 32-, and 14-kDa (RPA70, RPA32, RPA14, respectively). It is a protein essential for most cellular DNA metabolic pathways...
- Robison J, Bissler J, Dixon K. Replication protein A is required for etoposide-induced assembly of MRE11/RAD50/NBS1 complex repair foci. Cell Cycle. 2007;6:2408-16 pubmed..These data support a role for RPA as an initial signal/sensor for DNA damage that facilitates recruitment of MRN and ATM/ATR to sites of damage, where they then work together to fully activate the DNA damage response. ..
- Araya R, Hirai I, Meyerkord C, Wang H. Loss of RPA1 induces Chk2 phosphorylation through a caffeine-sensitive pathway. FEBS Lett. 2005;579:157-61 pubmed..In this study, we show that knockdown of RPA1 by siRNA duplexes induces ATM (Ser1981) and Chk2 (Thr68), but not Chk1 (Ser345) phosphorylation and results in p21 ..
- Sleeth K, Sørensen C, Issaeva N, Dziegielewski J, Bartek J, Helleday T. RPA mediates recombination repair during replication stress and is displaced from DNA by checkpoint signalling in human cells. J Mol Biol. 2007;373:38-47 pubmed..Furthermore, our data suggest that replacement of RPA with the RAD51 and RAD52 proteins is affected by checkpoint signalling. ..
- Manthey K, Opiyo S, Glanzer J, Dimitrova D, Elliott J, Oakley G. NBS1 mediates ATR-dependent RPA hyperphosphorylation following replication-fork stall and collapse. J Cell Sci. 2007;120:4221-9 pubmed..Our findings suggest that RPA hyperphosphorylation requires NBS1 and is important for the cellular response to DNA damage. ..
- Binz S, Sheehan A, Wold M. Replication protein A phosphorylation and the cellular response to DNA damage. DNA Repair (Amst). 2004;3:1015-24 pubmed..This suggests that the role of RPA phosphorylation in the cellular response to DNA damage is to help regulate DNA metabolism and promote DNA repair. ..
- Wood R. DNA damage recognition during nucleotide excision repair in mammalian cells. Biochimie. 1999;81:39-44 pubmed
- Iftode C, Daniely Y, Borowiec J. Replication protein A (RPA): the eukaryotic SSB. Crit Rev Biochem Mol Biol. 1999;34:141-80 pubmed
- Romanova L, Willers H, Blagosklonny M, Powell S. The interaction of p53 with replication protein A mediates suppression of homologous recombination. Oncogene. 2004;23:9025-33 pubmed..Our data support and extend the previously formulated 'dual model' of p53's role as guardian of the genome. ..
- Brosh R, Orren D, Nehlin J, Ravn P, Kenny M, Machwe A, et al. Functional and physical interaction between WRN helicase and human replication protein A. J Biol Chem. 1999;274:18341-50 pubmed..The physical and functional interaction between WRN and hRPA suggests that the two proteins may function together in vivo in a pathway of DNA metabolism such as replication, recombination, or repair. ..
- Vasquez K, Christensen J, Li L, Finch R, Glazer P. Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions. Proc Natl Acad Sci U S A. 2002;99:5848-53 pubmed..Addition of XPA decreases the nonspecific DNA aggregate formation. These results support the hypothesis that the NER machinery is targeted to helical distortions and demonstrate that RPA can recognize damaged DNA even without XPA. ..
- Guo S, Zhang Y, Yuan F, Gao Y, Gu L, Wong I, et al. Regulation of replication protein A functions in DNA mismatch repair by phosphorylation. J Biol Chem. 2006;281:21607-16 pubmed..These observations support a model of how phosphorylation alters the DNA binding affinity of RPA to fulfill its differential requirement at the various stages of MMR. ..
- Basu U, Chaudhuri J, Alpert C, Dutt S, Ranganath S, Li G, et al. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature. 2005;438:508-11 pubmed..We conclude that PKA has a critical role in post-translational regulation of AID activity in B cells. ..
- Jiang X, Klimovich V, Arunkumar A, Hysinger E, Wang Y, Ott R, et al. Structural mechanism of RPA loading on DNA during activation of a simple pre-replication complex. EMBO J. 2006;25:5516-26 pubmed..A mechanistic model is proposed in which the ternary complex is a key intermediate that directly couples origin DNA unwinding to RPA loading on emerging ssDNA. ..
- Golub E, Gupta R, Haaf T, Wold M, Radding C. Interaction of human rad51 recombination protein with single-stranded DNA binding protein, RPA. Nucleic Acids Res. 1998;26:5388-93 pubmed..The interactions of human RPA with Rad51, replication proteins and DNA are suited to the linking of recombination to replication. ..
- You J, Wang M, Lee S. Biochemical analysis of the damage recognition process in nucleotide excision repair. J Biol Chem. 2003;278:7476-85 pubmed..XPA and RPA, once forming a complex at the damage site, would likely work with TFIIH, XPG, and ERCC1-XPF for dual incision. ..
- Bochkarev A, Pfuetzner R, Edwards A, Frappier L. Structure of the single-stranded-DNA-binding domain of replication protein A bound to DNA. Nature. 1997;385:176-81 pubmed..Replication protein A is a heterotrimeric SSB that is highly conserved in eukaryotes. The largest subunit, RPA70, binds to single-stranded (ss)DNA and mediates interactions with many cellular and viral proteins...
- Shigechi T, Tomida J, Sato K, Kobayashi M, Eykelenboom J, Pessina F, et al. ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway. Cancer Res. 2012;72:1149-56 pubmed publisher..Together, our findings identify ATR as the kinase responsible for activating the FA pathway of DNA repair. ..
- Araújo S, Nigg E, Wood R. Strong functional interactions of TFIIH with XPC and XPG in human DNA nucleotide excision repair, without a preassembled repairosome. Mol Cell Biol. 2001;21:2281-91 pubmed..A panel of antibodies was used to estimate that there are on the order of 10(5) molecules of each core NER factor per HeLa cell. ..
- Quan J, Yusufzai T. HARP preferentially co-purifies with RPA bound to DNA-PK and blocks RPA phosphorylation. Epigenetics. 2014;9:693-7 pubmed publisher..Our results suggest that, in addition to its annealing helicase activity, which eliminates the natural binding substrate for RPA, HARP blocks the phosphorylation of RPA by DNA-PK. ..
- Miyake Y, Nakamura M, Nabetani A, Shimamura S, Tamura M, Yonehara S, et al. RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol Cell. 2009;36:193-206 pubmed publisher..We propose that CST is a replication protein A (RPA)-like complex that is not directly involved in conventional DNA replication at forks but plays a role in DNA metabolism frequently required by telomeres. ..
- Panero J, Stella F, Schutz N, Fantl D, Slavutsky I. Differential Expression of Non-Shelterin Genes Associated with High Telomerase Levels and Telomere Shortening in Plasma Cell Disorders. PLoS ONE. 2015;10:e0137972 pubmed publisher..the expression profile of a set of non-shelterin genes involved in essential processes such as replication (RPA1), DNA damage repair pathways (MRE11-RAD50-NBS1) and stabilization of telomerase complex (DKC1), in 35 patients with ..
- Ghospurkar P, Wilson T, Liu S, Herauf A, Steffes J, Mueller E, et al. Phosphorylation and cellular function of the human Rpa2 N-terminus in the budding yeast Saccharomyces cerevisiae. Exp Cell Res. 2015;331:183-99 pubmed publisher..The implication is that budding yeast represents a potential model system for studying not only human Rpa2 N-terminal phosphorylation, but also phosphorylation of Rpa2 N-termini from other eukaryotic organisms. ..
- Song X, Wang S, Hong X, Li X, Zhao X, Huai C, et al. Single nucleotide polymorphisms of nucleotide excision repair pathway are significantly associated with outcomes of platinum-based chemotherapy in lung cancer. Sci Rep. 2017;7:11785 pubmed publisher..The results showed that consecutive significant signals were observed in XPA, RPA1, POLD1, POLD3...
- Outwin E, Carpenter G, Bi W, Withers M, Lupski J, O Driscoll M. Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome. PLoS Genet. 2011;7:e1002247 pubmed publisher..We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR)...
- Tomida J, Itaya A, Shigechi T, Unno J, Uchida E, Ikura M, et al. A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair. Nucleic Acids Res. 2013;41:6930-41 pubmed publisher..Collectively, these data reveal new aspects of the interplay between regulation of ATR-ATRIP kinase and activation of the FA pathway. ..
- Machwe A, Lozada E, Wold M, Li G, Orren D. Molecular cooperation between the Werner syndrome protein and replication protein A in relation to replication fork blockage. J Biol Chem. 2011;286:3497-508 pubmed publisher..Taken together, our results suggest that, upon replication blockage, WRN and RPA functionally interact and cooperate to help properly resolve replication forks and maintain genome stability. ..
- Ni Z, Yao C, Zhu X, Gong C, Xu Z, Wang L, et al. Ailanthone inhibits non-small cell lung cancer cell growth through repressing DNA replication via downregulating RPA1. Br J Cancer. 2017;117:1621-1630 pubmed publisher..Aila dose-dependently decreased BrdU incorporation and downregulated the expression of replication protein A1 (RPA1)...
- Kemp M, Akan Z, Yilmaz S, Grillo M, Smith Roe S, Kang T, et al. Tipin-replication protein A interaction mediates Chk1 phosphorylation by ATR in response to genotoxic stress. J Biol Chem. 2010;285:16562-71 pubmed publisher..Our results therefore indicate that RPA-covered ssDNA not only supports recruitment and activation of ATR but also, through Tipin and Claspin, it plays an important role in the action of ATR on its critical downstream target Chk1. ..
- Chen R, Subramanyam S, Elcock A, Spies M, Wold M. Dynamic binding of replication protein a is required for DNA repair. Nucleic Acids Res. 2016;44:5758-72 pubmed publisher..It is likely that the binding modes are in equilibrium and reflect dynamics in the RPA-DNA complex. This suggests that dynamic binding of RPA to DNA is necessary for different cellular functions. ..
- Wan L, Huang J. The PSO4 protein complex associates with replication protein A (RPA) and modulates the activation of ataxia telangiectasia-mutated and Rad3-related (ATR). J Biol Chem. 2014;289:6619-26 pubmed publisher..Moreover, we demonstrate that both the RPA1-binding ability of BCAS2 and the E3 ligase activity of PSO4 are required for efficient accumulation of ATRIP at DNA ..
- Mollica P, Reid J, Ogle R, Sachs P, Bruno R. DNA Methylation Leads to DNA Repair Gene Down-Regulation and Trinucleotide Repeat Expansion in Patient-Derived Huntington Disease Cells. Am J Pathol. 2016;186:1967-1976 pubmed publisher..hypothesis, we analyzed expression of select DNA repair genes involved in mismatch/loop-out repair (APEX1, BRCA1, RPA1, and RPA3) in patient-derived HD cells and found each was consistently down-regulated relative to wild-type samples ..
- Meetei A, Sechi S, Wallisch M, Yang D, Young M, Joenje H, et al. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol Cell Biol. 2003;23:3417-26 pubmed..The findings that FA proteins are part of a DNA-unwinding complex imply that FA proteins may participate in DNA repair. ..
- Planchard D, Domont J, Taranchon E, Monnet I, Tredaniel J, Caliandro R, et al. The NER proteins are differentially expressed in ever smokers and in never smokers with lung adenocarcinoma. Ann Oncol. 2009;20:1257-63 pubmed publisher..7, 95% CI 1.5-33.3) and XPF levels (OR 12.5, 95% CI 2.9-50) after adjusting for age, sex and BAC features. In patients with resected lung AC, ERCC1, RPA and XPF expression levels are higher in NS compared with ES. ..
- Toledo L, Altmeyer M, Rask M, Lukas C, Larsen D, Povlsen L, et al. ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell. 2013;155:1088-103 pubmed publisher..Because cancer cells commonly feature intrinsically high replication stress, this study also provides a molecular rationale for their hypersensitivity to ATR inhibitors. ..
- Pabla N, Huang S, Mi Q, Daniel R, Dong Z. ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. J Biol Chem. 2008;283:6572-83 pubmed..Together, the results suggest an important role for the DNA damage response mediated by ATR-Chk2 in p53 activation and renal cell apoptosis during cisplatin nephrotoxicity. ..
- Tian F, Sharma S, Zou J, Lin S, Wang B, Rezvani K, et al. BRCA1 promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade. Proc Natl Acad Sci U S A. 2013;110:13558-63 pubmed publisher..Our data suggest that BRCA1 plays a critical role in promoting translesion DNA synthesis as well as DNA template switching. ..