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Gene Review

RFC1  -  replication factor C (activator 1) 1, 145kDa

Homo sapiens

Synonyms: A1, A1 140 kDa subunit, Activator 1 140 kDa subunit, Activator 1 large subunit, Activator 1 subunit 1, ...
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Disease relevance of RFC1

  • No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms [1].
  • More recently the large subunit of RFC, RFC (p140), has been found to interact with the retinoblastoma (Rb) tumor suppressor and the CCAAT/enhancer-binding protein alpha (C/EBP alpha) transcription factor [2].
  • In this report, we describe the purification and properties of recombinant human RFC expressed in Sf9 cells from baculovirus expression vectors [3].
  • However, it cannot substitute for RFC in promoting simian virus 40 DNA replication in vitro with crude fractions [4].
  • In this study, we hypothesised that genetic variants in RFC1 may modulate risk of oesophageal cancer (EC) and gastric cancer (GC) [5].

High impact information on RFC1

  • The clamp loader, replication factor C (RFC), can reverse this mark by unloading PCNA from the replicated DNA [6].
  • We have recently delineated a novel 38 amino acid transport signal in the hnRNP A1 protein, termed M9, which confers bidirectional transport across the nuclear envelope [7].
  • Transformation of RL01 with a vector p35A1, containing the A1-complementary DNA behind the 35S promotor leads to red flowers of the pelargonidin-type [8].
  • RL01 served as a recipient for the transfer of the A1 gene of Zea mays encoding dihydroquercetin 4-reductase, which can reduce dihydrokaempferol and thereby provided the intermediate for pelargonidin biosynthesis [8].
  • Most importantly, caspase activity results in a selective substrate specificity, since poly(ADP-ribose) polymerase (PARP), lamin B, and Wee1 kinase, but not DNA fragmentation factor (DFF45) or replication factor C (RFC140), are processed [9].

Chemical compound and disease context of RFC1


Biological context of RFC1


Anatomical context of RFC1

  • Replication factor C (RFC) is a five-subunit protein complex required for coordinate leading and lagging strand DNA synthesis during S phase and DNA repair in eukaryotic cells [3].
  • RFC1- as well as MTX-1-mediated uptake of a marker substrate into suitable human and rat cell lines increased with proton concentration, was sodium-dependent at neutral pH, and inhibited by folate at acidic pH [18].
  • In contrast, the effect of PGA1 on folic acid transport was small (approximately 20% inhibition of total influx), consistent with the observation that the major portion of folic acid transport in CHO cells is mediated by a low pH mechanism distinct from RFC1 [19].
  • We show that cleavage of RFC140 during Fas-mediated apoptosis in Jurkat cells and lymphocytes results in generation of multiple fragments [20].
  • Northern and/or in situ hybridization analysis of the A1 and A2 genes confirmed their restricted expression to the vessel endothelium [21].

Associations of RFC1 with chemical compounds

  • This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate [1].
  • Human RFC is a protein complex consisting of five distinct subunits that migrate through SDS/polyacrylamide gels as protein bands of 140, 40, 38, 37, and 36 kDa [15].
  • In this study, the arginine fingers in RFC were mutated to examine the steps in the PCNA loading mechanism that occur after RFC binds ATP [22].
  • Mutant RFC complexes containing rfc2-K71R or rfc3-K59R, carrying a conservative lysine --> arginine mutation, had much milder clamp loading defects that could be partially (rfc2-K71R) or completely (rfc3-K59R) suppressed at high ATP concentrations [23].
  • The MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms had no individual effects on serum tHcy or folate concentrations [16].

Physical interactions of RFC1


Enzymatic interactions of RFC1

  • On the other hand, the C-terminal truncated RFC inhibits the telomerase activity more than the N-terminal-deleted and full-length RFC p140 [26].

Regulatory relationships of RFC1

  • When Rad17 was co-expressed with the four small subunits of RFC in insect cells, these proteins formed a complex of 240 kDa that displayed DNA binding, ATPase activity and binding to its predicted target protein, Rad9-1-1 [27].
  • Thus, a certain interaction of the N- and C-terminal regions is considered to be required for RFC p140 to suppress telomerase activity [26].
  • Deletion of the p140 N-terminal half, including the DNA ligase homology domain, resulted in the formation of an RFC complex with enhanced activity in replication and PCNA loading [28].
  • In other systems, the heteropentameric RFC clamp loader complex stimulates loading of DNA polymerase delta to the primer-template [29].

Other interactions of RFC1

  • This report finds that the ATP sites of RFC function in distinct steps during loading of PCNA onto DNA [22].
  • Furthermore, RFC37, the third subunit of the RFC complex, competes with RIalpha and displaces it from the RFC40-RIalpha complex [30].
  • Clamp and clamp loader structures of the human checkpoint protein complexes, Rad9-1-1 and Rad17-RFC [27].
  • Introduction of an alanine at position 210 in place of an arginine also reduced the efficiency of PCNA in supporting RFC-dependent polymerase delta-catalyzed elongation of a singly primed DNA template [24].
  • The reconstituted human Chl12-RFC complex functions as a second PCNA loader [4].

Analytical, diagnostic and therapeutic context of RFC1

  • To test this hypothesis, we evaluated the associations of the G80A polymorphism of RFC1 with EC and GC risk in a case-control study of 216 EC and 633 GC cases and 673 cancer-free controls in a Chinese population [5].
  • Direct observation by electron microscopy reveals that RFC has a closed two-finger structure called the U form in the absence of ATP [31].
  • However, Southern blot analysis demonstrated no change in gene copy number nor gross rearrangement of RFC1 in the resistant cells [32].
  • The labeled blood group antigens (A1, A2, and B) thus produced were analyzed by sodium dodecyl sulfate gel electrophoresis and by isoelectric focusing [33].
  • After removal of adherent cells, early rosette-forming cells (early RFC), which were characterized by early (5 min) rosette formation with sheep blood cells (SRBC) at an SRBC to lymphocyte ratio of 8:1, were separated from nonrosetting cells by sedimentation on Ficoll-Hypaque gradient [34].


  1. Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma. Shimasaki, N., Mori, T., Samejima, H., Sato, R., Shimada, H., Yahagi, N., Torii, C., Yoshihara, H., Tanigawara, Y., Takahashi, T., Kosaki, K. J. Pediatr. Hematol. Oncol. (2006) [Pubmed]
  2. The large subunit of replication factor C interacts with the histone deacetylase, HDAC1. Anderson, L.A., Perkins, N.D. J. Biol. Chem. (2002) [Pubmed]
  3. Reconstitution of recombinant human replication factor C (RFC) and identification of an RFC subcomplex possessing DNA-dependent ATPase activity. Ellison, V., Stillman, B. J. Biol. Chem. (1998) [Pubmed]
  4. The reconstituted human Chl12-RFC complex functions as a second PCNA loader. Shiomi, Y., Shinozaki, A., Sugimoto, K., Usukura, J., Obuse, C., Tsurimoto, T. Genes Cells (2004) [Pubmed]
  5. Reduced folate carrier gene G80A polymorphism is associated with an increased risk of gastroesophageal cancers in a chinese population. Wang, L., Chen, W., Wang, J., Tan, Y., Zhou, Y., Ding, W., Hua, Z., Shen, J., Xu, Y., Shen, H. Eur. J. Cancer (2006) [Pubmed]
  6. Replication-dependent marking of DNA by PCNA facilitates CAF-1-coupled inheritance of chromatin. Shibahara, K., Stillman, B. Cell (1999) [Pubmed]
  7. A novel receptor-mediated nuclear protein import pathway. Pollard, V.W., Michael, W.M., Nakielny, S., Siomi, M.C., Wang, F., Dreyfuss, G. Cell (1996) [Pubmed]
  8. A new petunia flower colour generated by transformation of a mutant with a maize gene. Meyer, P., Heidmann, I., Forkmann, G., Saedler, H. Nature (1987) [Pubmed]
  9. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. Alam, A., Cohen, L.Y., Aouad, S., Sékaly, R.P. J. Exp. Med. (1999) [Pubmed]
  10. Genetic Variation of Infant Reduced Folate Carrier (A80G) and Risk of Orofacial Defects and Congenital Heart Defects in China. Pei, L., Zhu, H., Zhu, J., Ren, A., Finnell, R.H., Li, Z. Annals of epidemiology. (2006) [Pubmed]
  11. Characterization of genetic markers in the 5'flanking region of the apo A1 gene. Shoulders, C.C., Narcisi, T.M., Jarmuz, A., Brett, D.J., Bayliss, J.D., Scott, J. Hum. Genet. (1993) [Pubmed]
  12. Lipoprotein immune complexes as markers of atherosclerosis. Orekhov, A.N., Kalenich, O.S., Tertov, V.V., Novikov, I.D. International journal of tissue reactions. (1991) [Pubmed]
  13. Decreased autologous rosette-forming T lymphocytes in alcoholic cirrhosis: absence of correlation with other T cell markers and with delayed cutaneous hypersensitivity. Lang, J.M., Ruscher, H., Hasselmann, J.P., Grandjean, P., Bigel, P., Mayer, S. Int. Arch. Allergy Appl. Immunol. (1980) [Pubmed]
  14. Targeted scan of fifteen regions for nonsyndromic cleft lip and palate in Filipino families. Schultz, R.E., Cooper, M.E., Daack-Hirsch, S., Shi, M., Nepomucena, B., Graf, K.A., O'Brien, E.K., O'Brien, S.E., Marazita, M.L., Murray, J.C. Am. J. Med. Genet. A (2004) [Pubmed]
  15. In vitro reconstitution of human replication factor C from its five subunits. Uhlmann, F., Cai, J., Flores-Rozas, H., Dean, F.B., Finkelstein, J., O'Donnell, M., Hurwitz, J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  16. Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population. Devlin, A.M., Clarke, R., Birks, J., Evans, J.G., Halsted, C.H. Am. J. Clin. Nutr. (2006) [Pubmed]
  17. Cyclin-dependent kinase inhibitor p21 modulates the DNA primer-template recognition complex. Waga, S., Stillman, B. Mol. Cell. Biol. (1998) [Pubmed]
  18. The H(+)-dependent reduced folate carrier 1 of humans and the sodium-dependent methotrexate carrier-1 of the rat are orthologs. Kneuer, C., Honscha, W. FEBS Lett. (2004) [Pubmed]
  19. Inhibitory effects of prostaglandin A1 on membrane transport of folates mediated by both the reduced folate carrier and ATP-driven exporters. Assaraf, Y.G., Sierra, E.E., Babani, S., Goldman, I.D. Biochem. Pharmacol. (1999) [Pubmed]
  20. The large subunit of replication factor C is a substrate for caspase-3 in vitro and is cleaved by a caspase-3-like protease during Fas-mediated apoptosis. Rhéaume, E., Cohen, L.Y., Uhlmann, F., Lazure, C., Alam, A., Hurwitz, J., Sékaly, R.P., Denis, F. EMBO J. (1997) [Pubmed]
  21. Alterations in gene expression associated with changes in the state of endothelial differentiation. Shima, D.T., Saunders, K.B., Gougos, A., D'Amore, P.A. Differentiation (1995) [Pubmed]
  22. The replication factor C clamp loader requires arginine finger sensors to drive DNA binding and proliferating cell nuclear antigen loading. Johnson, A., Yao, N.Y., Bowman, G.D., Kuriyan, J., O'donnell, M. J. Biol. Chem. (2006) [Pubmed]
  23. ATP utilization by yeast replication factor C. III. The ATP-binding domains of Rfc2, Rfc3, and Rfc4 are essential for DNA recognition and clamp loading. Schmidt, S.L., Gomes, X.V., Burgers, P.M. J. Biol. Chem. (2001) [Pubmed]
  24. Studies on the interactions between human replication factor C and human proliferating cell nuclear antigen. Zhang, G., Gibbs, E., Kelman, Z., O'Donnell, M., Hurwitz, J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  25. Regulation of RelA (p65) function by the large subunit of replication factor C. Anderson, L.A., Perkins, N.D. Mol. Cell. Biol. (2003) [Pubmed]
  26. Characterization of telomere-binding activity of replication factor C large subunit p140. Uchiumi, F., Watanabe, M., Tanuma, S. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  27. Clamp and clamp loader structures of the human checkpoint protein complexes, Rad9-1-1 and Rad17-RFC. Shiomi, Y., Shinozaki, A., Nakada, D., Sugimoto, K., Usukura, J., Obuse, C., Tsurimoto, T. Genes Cells (2002) [Pubmed]
  28. Deletion analysis of the large subunit p140 in human replication factor C reveals regions required for complex formation and replication activities. Uhlmann, F., Cai, J., Gibbs, E., O'Donnell, M., Hurwitz, J. J. Biol. Chem. (1997) [Pubmed]
  29. Interaction of geminivirus Rep protein with replication factor C and its potential role during geminivirus DNA replication. Luque, A., Sanz-Burgos, A.P., Ramirez-Parra, E., Castellano, M.M., Gutierrez, C. Virology (2002) [Pubmed]
  30. The second subunit of the replication factor C complex (RFC40) and the regulatory subunit (RIalpha) of protein kinase A form a protein complex promoting cell survival. Gupte, R.S., Weng, Y., Liu, L., Lee, M.Y. Cell Cycle (2005) [Pubmed]
  31. ATP-dependent structural change of the eukaryotic clamp-loader protein, replication factor C. Shiomi, Y., Usukura, J., Masamura, Y., Takeyasu, K., Nakayama, Y., Obuse, C., Yoshikawa, H., Tsurimoto, T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  32. Molecular characterization of human acute leukemia cell line resistant to ZD9331, a non-polyglutamatable thymidylate synthase inhibitor. Kobayashi, H., Takemura, Y., Miyachi, H. Cancer Chemother. Pharmacol. (1998) [Pubmed]
  33. Multiple components of blood group A and B antigens in human erythrocyte membranes and their difference between A1 and A2 status. Fujii, H., Yoshida, A. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  34. Mitogenic responsiveness and monocyte-lymphocyte interaction of early and late rosette-forming cell populations of human peripheral blood lymphocytes. Taniguchi, N., Miyawaki, T., Moriya, N., Nagaoki, T., Kato, E. J. Immunol. (1977) [Pubmed]
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