RFC1 explained

Replication factor C subunit 1 is a protein that in humans is encoded by the RFC1 gene.^{[1] [2]}

Function

The protein encoded by this gene is the large subunit of replication factor C, which is a five subunit DNA polymerase accessory protein. Replication factor C is a DNA-dependent ATPase that is required for eukaryotic DNA replication and repair. The protein acts as an activator of DNA polymerases, binds to the 3' end of primers, and promotes coordinated synthesis of both strands. It also may have a role in telomere stability.

Interactions

RFC1 has been shown to interact with:

• BRD4,^[3]
• HDAC1,^[4]
• PCNA,^{[3] [5] [6] [7] [8]}
• RELA^[9] and
• RFC3.^{[10] [11] [12]}

Clinical relevance

Biallelic intronic repeat expansions (a series of repeating nucleotide sequences) in the replication factor C subunit 1 (RFC1) gene causes cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS).^[13] Within the poly(A) tail of an AluSx3 element in RFC1, there are eleven repeats of the pentanucleotide "AAAAG". Repeat expansion and polymorphic configuration are observed in part of the population, with increased number of repeats associated to alternative "AAAGG", "AAGGG" and "ACAGG" pentanucleotides.^[14] In particular, biallelic "AAGGG" and "ACAGG" repeat expansion have disproportionately been observed in patients with CANVAS. Biallelic "AAGGG" repeat expansion is also reported in a high number of sporadic cases of late-onset ataxia, isolate sensory neuropathy^{[15] [16]} and, less frequently, isolate cerebellar ataxia.^[17] Due to a diagnostic overlap with CANVAS, researchers have also investigated the presence of RFC1 expansions in pathologically confirmed multiple system atrophy (MSA) but found a similar alteration frequency (0.7%) to a healthy population, suggesting RFC1 does not have a role in this disease.^[18]

Mutant biallelic intronic repeat expansions do not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function of this gene.

In patients with the pathogenic RFC1 expansion, sensory neuropathy appears to be a predominant feature and patients may also present with symptoms such as cerebellar dysfunction, vestibular involvement and a dry spasmodic cough therefore, genetic testing is recommended in those with these symptoms.^[19]

Further reading

• Lu Y, Riegel AT . The human DNA-binding protein, PO-GA, is homologous to the large subunit of mouse replication factor C: regulation by alternate 3' processing of mRNA . Gene . 145 . 2 . 261–5 . August 1994 . 7914507 . 10.1016/0378-1119(94)90017-5 .
• Bunz F, Kobayashi R, Stillman B . cDNAs encoding the large subunit of human replication factor C . Proceedings of the National Academy of Sciences of the United States of America . 90 . 23 . 11014–8 . December 1993 . 8248204 . 47912 . 10.1073/pnas.90.23.11014 . 1993PNAS...9011014B . free .
• Lu Y, Zeft AS, Riegel AT . Cloning and expression of a novel human DNA binding protein, PO-GA . Biochemical and Biophysical Research Communications . 193 . 2 . 779–86 . June 1993 . 8512577 . 10.1006/bbrc.1993.1693 . free .
• Uhlmann F, Cai J, Flores-Rozas H, Dean FB, Finkelstein J, O'Donnell M, Hurwitz J . In vitro reconstitution of human replication factor C from its five subunits . Proceedings of the National Academy of Sciences of the United States of America . 93 . 13 . 6521–6 . June 1996 . 8692848 . 39056 . 10.1073/pnas.93.13.6521 . 1996PNAS...93.6521U . free .
• Fotedar R, Mossi R, Fitzgerald P, Rousselle T, Maga G, Brickner H, Messier H, Kasibhatla S, Hübscher U, Fotedar A . 6 . A conserved domain of the large subunit of replication factor C binds PCNA and acts like a dominant negative inhibitor of DNA replication in mammalian cells . The EMBO Journal . 15 . 16 . 4423–33 . August 1996 . 8861969 . 452166 . 10.1002/j.1460-2075.1996.tb00815.x .
• Uchiumi F, Ohta T, Tanuma S . Replication factor C recognizes 5'-phosphate ends of telomeres . Biochemical and Biophysical Research Communications . 229 . 1 . 310–5 . December 1996 . 8954124 . 10.1006/bbrc.1996.1798 .
• Mossi R, Jónsson ZO, Allen BL, Hardin SH, Hübscher U . Replication factor C interacts with the C-terminal side of proliferating cell nuclear antigen . The Journal of Biological Chemistry . 272 . 3 . 1769–76 . January 1997 . 8999859 . 10.1074/jbc.272.3.1769 . free .
• Cujec TP, Cho H, Maldonado E, Meyer J, Reinberg D, Peterlin BM . The human immunodeficiency virus transactivator Tat interacts with the RNA polymerase II holoenzyme . Molecular and Cellular Biology . 17 . 4 . 1817–23 . April 1997 . 9121429 . 232028 . 10.1128/mcb.17.4.1817 .
• Ubeda M, Habener JF . The large subunit of the DNA replication complex C (DSEB/RF-C140) cleaved and inactivated by caspase-3 (CPP32/YAMA) during Fas-induced apoptosis . The Journal of Biological Chemistry . 272 . 31 . 19562–8 . August 1997 . 9235961 . 10.1074/jbc.272.31.19562 . free .
• Rhéaume E, Cohen LY, Uhlmann F, Lazure C, Alam A, Hurwitz J, Sékaly RP, Denis F . 6 . 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 . The EMBO Journal . 16 . 21 . 6346–54 . November 1997 . 9351817 . 1170241 . 10.1093/emboj/16.21.6346 .
• Ellison V, Stillman B . Reconstitution of recombinant human replication factor C (RFC) and identification of an RFC subcomplex possessing DNA-dependent ATPase activity . The Journal of Biological Chemistry . 273 . 10 . 5979–87 . March 1998 . 9488738 . 10.1074/jbc.273.10.5979 . free .
• Coll JM, Hickey RJ, Cronkey EA, Jiang HY, Schnaper L, Lee MY, Uitto L, Syvaoja JE, Malkas LH . 6 . Mapping specific protein-protein interactions within the core component of the breast cell DNA synthesome . Oncology Research . 9 . 11–12 . 629–39 . 1998 . 9563011 .
• Allen BL, Uhlmann F, Gaur LK, Mulder BA, Posey KL, Jones LB, Hardin SH . DNA recognition properties of the N-terminal DNA binding domain within the large subunit of replication factor C . Nucleic Acids Research . 26 . 17 . 3877–82 . September 1998 . 9705493 . 147807 . 10.1093/nar/26.17.3877 .
• van der Kuip H, Carius B, Haque SJ, Williams BR, Huber C, Fischer T . 22183443 . The DNA-binding subunit p140 of replication factor C is upregulated in cycling cells and associates with G1 phase cell cycle regulatory proteins . Journal of Molecular Medicine . 77 . 4 . 386–92 . April 1999 . 10353443 . 10.1007/s001090050365 .
• Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J . BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures . Genes & Development . 14 . 8 . 927–39 . April 2000 . 10783165 . 316544 . 10.1101/gad.14.8.927 .
• Eva Y.-H. P. Lee . Yazdi PT, Wang Y, Zhao S, Patel N, Lee EY, Qin J . SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint . Genes & Development . 16 . 5 . 571–82 . March 2002 . 11877377 . 155356 . 10.1101/gad.970702 .
• Anderson LA, Perkins ND . The large subunit of replication factor C interacts with the histone deacetylase, HDAC1 . The Journal of Biological Chemistry . 277 . 33 . 29550–4 . August 2002 . 12045192 . 10.1074/jbc.M200513200 . free .
• Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T . A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein . The Journal of Biological Chemistry . 277 . 43 . 40362–7 . October 2002 . 12171929 . 10.1074/jbc.M206194200 . free .
• Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K . 6 . A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase . Molecular and Cellular Biology . 22 . 18 . 6509–20 . September 2002 . 12192049 . 135621 . 10.1128/MCB.22.18.6509-6520.2002 .

Notes and References

1. Luckow B, Bunz F, Stillman B, Lichter P, Schütz G . Cloning, expression, and chromosomal localization of the 140-kilodalton subunit of replication factor C from mice and humans . Molecular and Cellular Biology . 14 . 3 . 1626–34 . March 1994 . 8114700 . 358521 . 10.1128/mcb.14.3.1626 .
2. Web site: Entrez Gene: RFC1 replication factor C (activator 1) 1, 145kDa.
3. Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K . 6 . A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase . Molecular and Cellular Biology . 22 . 18 . 6509–20 . September 2002 . 12192049 . 135621 . 10.1128/mcb.22.18.6509-6520.2002 .
4. Anderson LA, Perkins ND . The large subunit of replication factor C interacts with the histone deacetylase, HDAC1 . The Journal of Biological Chemistry . 277 . 33 . 29550–4 . August 2002 . 12045192 . 10.1074/jbc.M200513200 . free .
5. Fotedar R, Mossi R, Fitzgerald P, Rousselle T, Maga G, Brickner H, Messier H, Kasibhatla S, Hübscher U, Fotedar A . 6 . A conserved domain of the large subunit of replication factor C binds PCNA and acts like a dominant negative inhibitor of DNA replication in mammalian cells . The EMBO Journal . 15 . 16 . 4423–33 . August 1996 . 8861969 . 452166 . 10.1002/j.1460-2075.1996.tb00815.x .
6. Mossi R, Jónsson ZO, Allen BL, Hardin SH, Hübscher U . Replication factor C interacts with the C-terminal side of proliferating cell nuclear antigen . The Journal of Biological Chemistry . 272 . 3 . 1769–76 . January 1997 . 8999859 . 10.1074/jbc.272.3.1769 . free .
7. van der Kuip H, Carius B, Haque SJ, Williams BR, Huber C, Fischer T . 22183443 . The DNA-binding subunit p140 of replication factor C is upregulated in cycling cells and associates with G1 phase cell cycle regulatory proteins . Journal of Molecular Medicine . 77 . 4 . 386–92 . April 1999 . 10353443 . 10.1007/s001090050365 .
8. Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T . A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein . The Journal of Biological Chemistry . 277 . 43 . 40362–7 . October 2002 . 12171929 . 10.1074/jbc.M206194200 . free .
9. Anderson LA, Perkins ND . Regulation of RelA (p65) function by the large subunit of replication factor C . Molecular and Cellular Biology . 23 . 2 . 721–32 . January 2003 . 12509469 . 151544 . 10.1128/mcb.23.2.721-732.2003 .
10. Ellison V, Stillman B . Reconstitution of recombinant human replication factor C (RFC) and identification of an RFC subcomplex possessing DNA-dependent ATPase activity . The Journal of Biological Chemistry . 273 . 10 . 5979–87 . March 1998 . 9488738 . 10.1074/jbc.273.10.5979 . free .
11. Uhlmann F, Cai J, Flores-Rozas H, Dean FB, Finkelstein J, O'Donnell M, Hurwitz J . In vitro reconstitution of human replication factor C from its five subunits . Proceedings of the National Academy of Sciences of the United States of America . 93 . 13 . 6521–6 . June 1996 . 8692848 . 39056 . 10.1073/pnas.93.13.6521 . 1996PNAS...93.6521U . free .
12. Tomida J, Masuda Y, Hiroaki H, Ishikawa T, Song I, Tsurimoto T, Tateishi S, Shiomi T, Kamei Y, Kim J, Kamiya K, Vaziri C, Ohmori H, Todo T . 6 . DNA damage-induced ubiquitylation of RFC2 subunit of replication factor C complex . The Journal of Biological Chemistry . 283 . 14 . 9071–9 . April 2008 . 18245774 . 2431014 . 10.1074/jbc.M709835200 . free .
13. Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden H . 6 . Author Correction: Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia . Nature Genetics . 51 . 5 . 920 . May 2019 . 31028356 . 6730635 . 10.1038/s41588-019-0422-y .
14. Scriba CK, Beecroft SJ, Clayton JS, Cortese A, Sullivan R, Yau WY, Dominik N, Rodrigues M, Walker E, Dyer Z, Wu TY, Davis MR, Chandler DC, Weisburd B, Houlden H, Reilly MM, Laing NG, Lamont PJ, Roxburgh RH, Ravenscroft G . A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families . Brain . 143 . 2904–10 . October 2020 . 10 . 33103729 . 10.1093/brain/awaa263 . 7780484 .
15. Tagliapietra M, Cardellini D, Ferrarini M, Testi S, Ferrari S, Monaco S, Cavallaro T, Fabrizi GM . RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy . Journal of Neurology . April 2021 . 268 . 11 . 4280–4290 . 33884451 . 10.1007/s00415-021-10552-3 . 8505379 . free .
16. Currò R, Salvalaggio A, Tozza S, Gemelli C, Dominik N, Galassi Deforie V, Magrinelli F, Castellani F, Vegezzi E, Businaro P, Callegari I, Pichiecchio A, Cosentino G, Alfonsi E, Marchioni E, Colnaghi S, Gana S, Valente EM, Tassorelli C, Efthymiou S, Facchini S, Carr A, Laura M, Rossor AM, Manji H, Lunn MP, Pegoraro E, Santoro L, Grandis M, Bellone E, Beauchamp NJ, Hadjivassiliou M, Kaski D, Bronstein AM, Houlden H, Reilly MM, Mandich P, Schenone A, Manganelli F, Briani C . RFC1 expansions are a common cause of idiopathic sensory neuropathy . Brain . 144 . 5 . 2904–10 . June 2021 . 33969391 . 10.1093/brain/awab072 . 0006-8950 . 8262986 . free .
17. Traschütz A, Cortese A, Reich S, Dominik N, Faber J, Jacobi H, Hartmann AM, Rujescu D, Montaut S, Echaniz-Laguna A, Erer S, Schütz VC, Tarnutzer AA, Sturm M, Haack TB, Vaucamps-Diedhiou N, Puccio H, Schöls L, Klockgether T, van de Warrenburg BP, Paucar M, Timmann D, Hilgers RD, Gazulla J, Strupp M, Moris G, Filla A, Houlden H, Anheim M, Infante J, Basak AN, Synofzik M . 6 . Group R study . Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1-disease . Neurology . 96 . 9 . e1369–e1382 . March 2021 . 33495376 . 10.1212/WNL.0000000000011528 . 8055326 . free .
18. Sullivan R, Yau WY, Chelban V, Rossi S, O'Connor E, Wood NW, Cortese A, Houlden H . 6 . RFC1 Intronic Repeat Expansions Absent in Pathologically Confirmed Multiple Systems Atrophy . Movement Disorders . April 2020 . 35 . 7 . 1277–1279 . 32333430 . 10.1002/mds.28074 . 216129457 .
19. Cortese A, Tozza S, Yau WY, Rossi S, Beecroft SJ, Jaunmuktane Z, Dyer Z, Ravenscroft G, Lamont PJ, Mossman S, Chancellor A, Maisonobe T, Pereon Y, Cauquil C, Colnaghi S, Mallucci G, Curro R, Tomaselli PJ, Thomas-Black G, Sullivan R, Efthymiou S, Rossor AM, Laurá M, Pipis M, Horga A, Polke J, Kaski D, Horvath R, Chinnery PF, Marques W, Tassorelli C, Devigili G, Leonardis L, Wood NW, Bronstein A, Giunti P, Züchner S, Stojkovic T, Laing N, Roxburgh RH, Houlden H, Reilly MM . 6 . Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion . Brain . 143 . 2 . 480–490 . February 2020 . 32040566 . 7009469 . 10.1093/brain/awz418 .