RAD51C

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External IDsGeneCards: [1]
Orthologs
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RAD51 homolog C (S. cerevisiae), also known as RAD51C, is a protein which in humans is encoded by the RAD51C gene.[1][2]

Function

The RAD51C protein is one of five paralogs of RAD51, including RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and each other.[3]

The RAD51 paralogs are all required for efficient DNA double-strand break repair by homologous recombination and depletion of any paralog results in significant decreases in homologous recombination frequency.[4]

RAD51C forms two distinct complexes with other related paralogs: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). These two complexes act at two different stages of homologous recombinational DNA repair. The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[4] The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament.

The CX3 complex acts downstream of RAD51 recruitment to damage sites.[4] The CX3 complex was shown to associate with Holliday junction resolvase activity, probably in a role of stabilizing gene conversion tracts.[4]

The RAD51C gene is one of genes four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors.[5] Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing has been observed for this gene and two variants encoding different isoforms have been identified.[1]

Clinical significance

A characteristic of many cancer cells is that parts of some genes contained within these cells have been recombined with other genes. One such gene fusion that has been identified in a MCF-7 breast cancer cell line is a chimera between the RAD51C and ATXN7 genes.[6][7] Since the RAD51C protein is involved in repairing double strand chromosome breaks, this chromosomal rearrangement could be responsible for the other rearrangements.[7]

Mutation, splicing, and epigenetic deficiency in cancer

RAD51C mutation increases the risk for breast and ovarian cancer, and was first established as a human cancer susceptibility gene in 2010.[8][9][10] Carriers of an RAD51C mutation had a 5.2-fold increased risk of ovarian cancer, indicating that RAD51C is a moderate ovarian cancer susceptibility gene.[11] A pathogenic mutation of RAD51C was present in approximately 1% to 3% of unselected ovarian cancers, and among mutation carriers, the lifetime risk of ovarian cancer was approximately 10-15%.[12][13][14][15]

In addition, there are three other causes of RAD51C deficiency that also appear to increase cancer risk. These are alternative splicing, promoter methylation and repression by over-expression of EZH2.

Three alternatively spliced RAD51C transcripts were identified in colorectal cancers. Variant 1 is joined from the 3' end of exon-6 to the 5' end of exon-8, variant 2 is joined at the 3' end of exon-5 to the 5' end of exon-8, and variant 3 is joined from the 3' end of exon-6 to the 5' end of exon-9.[16] Presence and mRNA expression of variant 1 RAD51C was found in 47% of colorectal cancers. Variant 1 mRNA was expressed about 5-fold more frequently in colorectal tumors than in non-tumor tissues, and when present, was expressed 8-fold more frequently than wild-type RAD51C mRNA. The authors concluded that variant 1 mRNA was associated with the malignant phenotype of colorectal cancers[16]

In the case of gastric cancer, reduced expression of RAD51C was found in about 40% to 50% of tumors, and almost all tumors with reduced RAD51C expression had methylation of the RAD51C promoter.[17] On the other hand, methylation of the RAD51C promoter was only found in about 1.5% of ovarian cancer cases.[13]

EZH2 protein is up-regulated in numerous cancers.[18][19] EZH2 mRNA is up-regulated, on average, 7.5-fold in breast cancer, and between 40% to 75% of breast cancers have over-expressed EZH2 protein.[20] EZH2 is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2) which catalyzes methylation of histone H3 at lysine 27 (H3K27me) and mediates epigenetic gene silencing of target genes via local chromatin reorganization.[19] EZH2 targets RAD51C, reducing RAD51C mRNA and protein expression (and also represses other RAD51 paralogs RAD51B, RAD51D, XRCC2 and XRCC3).[21] Increased expression of EZH2, leading to repression of RAD51 paralogs and consequent reduced homologous recombinational repair, was proposed as a cause of breast cancer.[22]

Interactions

RAD51C has been shown to interact with:

References

  1. ↑ 1.0 1.1 "Entrez Gene: RAD51C RAD51 homolog C (S. cerevisiae)".
  2. ↑ Dosanjh MK, Collins DW, Fan W, Lennon GG, Albala JS, Shen Z, Schild D (March 1998). "Isolation and characterization of RAD51C, a new human member of the RAD51 family of related genes". Nucleic Acids Research. 26 (5): 1179–84. doi:10.1093/nar/26.5.1179. PMC 147393. PMID 9469824.
  3. ↑ Miller KA, Sawicka D, Barsky D, Albala JS (2004). "Domain mapping of the Rad51 paralog protein complexes". Nucleic Acids Research. 32 (1): 169–78. doi:10.1093/nar/gkg925. PMC 373258. PMID 14704354.
  4. ↑ 4.0 4.1 4.2 4.3 Chun J, Buechelmaier ES, Powell SN (January 2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Molecular and Cellular Biology. 33 (2): 387–95. doi:10.1128/MCB.00465-12. PMC 3554112. PMID 23149936.
  5. ↑ Wu GJ, Sinclair CS, Paape J, Ingle JN, Roche PC, James CD, Couch FJ (October 2000). "17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes". Cancer Research. 60 (19): 5371–5. PMID 11034073.
  6. ↑ Wade N (2008-12-25). "The Chaos Inside a Cancer Cell". Science Visuals. NYTimes.com. Retrieved 2008-12-29.
  7. ↑ 7.0 7.1 Hampton OA, Den Hollander P, Miller CA, Delgado DA, Li J, Coarfa C, Harris RA, Richards S, Scherer SE, Muzny DM, Gibbs RA, Lee AV, Milosavljevic A (February 2009). "A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome". Genome Research. 19 (2): 167–77. doi:10.1101/gr.080259.108. PMC 2652200. PMID 19056696.
  8. ↑ Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H (May 2010). "Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene". Nature Genetics. 42 (5): 410–4. doi:10.1038/ng.569. PMID 20400964.
  9. ↑ Clague J, Wilhoite G, Adamson A, Bailis A, Weitzel JN, Neuhausen SL (2011). "RAD51C germline mutations in breast and ovarian cancer cases from high-risk families". PLOS One. 6 (9): e25632. doi:10.1371/journal.pone.0025632. PMC 3182241. PMID 21980511.
  10. ↑ Jønson L, Ahlborn LB, Steffensen AY, Djursby M, Ejlertsen B, Timshel S, Nielsen FC, Gerdes AM, Hansen TV (January 2016). "Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer". Breast Cancer Research and Treatment. 155 (2): 215–22. doi:10.1007/s10549-015-3674-y. PMID 26740214.
  11. ↑ Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, Edlund CK, Conti D, Harrington P, Fraser L, Philpott S, Anderson C, Rosenthal A, Gentry-Maharaj A, Bowtell DD, Alsop K, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Høgdall E, Høgdall CK, Jensen A, Kjaer SK, Lubiński J, Huzarski T, Jakubowska A, Gronwald J, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Odunsi K, Goode EL, Menon U, Jacobs IJ, Gayther SA, Pharoah PD (September 2015). "Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population". Journal of Clinical Oncology. 33 (26): 2901–7. doi:10.1200/JCO.2015.61.2408. PMC 4554751. PMID 26261251.
  12. ↑ Sopik V, Akbari MR, Narod SA (October 2015). "Genetic testing for RAD51C mutations: in the clinic and community". Clinical Genetics. 88 (4): 303–12. doi:10.1111/cge.12548. PMID 25470109.
  13. ↑ 13.0 13.1 Cunningham JM, Cicek MS, Larson NB, Davila J, Wang C, Larson MC, Song H, Dicks EM, Harrington P, Wick M, Winterhoff BJ, Hamidi H, Konecny GE, Chien J, Bibikova M, Fan JB, Kalli KR, Lindor NM, Fridley BL, Pharoah PP, Goode EL (February 2014). "Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status". Scientific Reports. 4: 4026. doi:10.1038/srep04026. PMC 4168524. PMID 24504028.
  14. ↑ Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King MC, Swisher EM (February 2014). "Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas". Clinical Cancer Research. 20 (3): 764–75. doi:10.1158/1078-0432.CCR-13-2287. PMC 3944197. PMID 24240112.
  15. ↑ Ring KL, Garcia C, Thomas MH, Modesitt SC (November 2017). "Current and future role of genetic screening in gynecologic malignancies". American Journal of Obstetrics and Gynecology. 217 (5): 512–521. doi:10.1016/j.ajog.2017.04.011. PMID 28411145.
  16. ↑ 16.0 16.1 Kalvala A, Gao L, Aguila B, Reese T, Otterson GA, Villalona-Calero MA, Duan W (April 2015). "Overexpression of Rad51C splice variants in colorectal tumors". Oncotarget. 6 (11): 8777–87. doi:10.18632/oncotarget.3209. PMC 4496183. PMID 25669972.
  17. ↑ Min A, Im SA, Yoon YK, Song SH, Nam HJ, Hur HS, Kim HP, Lee KH, Han SW, Oh DY, Kim TY, O'Connor MJ, Kim WH, Bang YJ (June 2013). "RAD51C-deficient cancer cells are highly sensitive to the PARP inhibitor olaparib". Molecular Cancer Therapeutics. 12 (6): 865–77. doi:10.1158/1535-7163.MCT-12-0950. PMID 23512992.
  18. ↑ Chang CJ, Hung MC (January 2012). "The role of EZH2 in tumour progression". British Journal of Cancer. 106 (2): 243–7. doi:10.1038/bjc.2011.551. PMC 3261672. PMID 22187039.
  19. ↑ 19.0 19.1 Völkel P, Dupret B, Le Bourhis X, Angrand PO (2015). "Diverse involvement of EZH2 in cancer epigenetics". American Journal of Translational Research. 7 (2): 175–93. PMC 4399085. PMID 25901190.
  20. ↑ Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM (September 2003). "EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells". Proceedings of the National Academy of Sciences of the United States of America. 100 (20): 11606–11. doi:10.1073/pnas.1933744100. PMC 208805. PMID 14500907.
  21. ↑ Zeidler M, Varambally S, Cao Q, Chinnaiyan AM, Ferguson DO, Merajver SD, Kleer CG (November 2005). "The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells". Neoplasia. 7 (11): 1011–9. doi:10.1593/neo.05472. PMC 1502020. PMID 16331887.
  22. ↑ Zeidler M, Kleer CG (September 2006). "The Polycomb group protein Enhancer of Zeste 2: its links to DNA repair and breast cancer". Journal of Molecular Histology. 37 (5–7): 219–23. doi:10.1007/s10735-006-9042-9. PMID 16855786.
  23. ↑ 23.0 23.1 Hussain S, Wilson JB, Medhurst AL, Hejna J, Witt E, Ananth S, Davies A, Masson JY, Moses R, West SC, de Winter JP, Ashworth A, Jones NJ, Mathew CG (June 2004). "Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways". Human Molecular Genetics. 13 (12): 1241–8. doi:10.1093/hmg/ddh135. PMID 15115758.
  24. ↑ 24.0 24.1 24.2 24.3 Miller KA, Yoshikawa DM, McConnell IR, Clark R, Schild D, Albala JS (March 2002). "RAD51C interacts with RAD51B and is central to a larger protein complex in vivo exclusive of RAD51". The Journal of Biological Chemistry. 277 (10): 8406–11. doi:10.1074/jbc.M108306200. PMID 11744692.
  25. ↑ Sigurdsson S, Van Komen S, Bussen W, Schild D, Albala JS, Sung P (December 2001). "Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange". Genes & Development. 15 (24): 3308–18. doi:10.1101/gad.935501. PMC 312844. PMID 11751636.
  26. ↑ 26.0 26.1 26.2 Liu N, Schild D, Thelen MP, Thompson LH (February 2002). "Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells". Nucleic Acids Research. 30 (4): 1009–15. doi:10.1093/nar/30.4.1009. PMC 100342. PMID 11842113.
  27. ↑ Kurumizaka H, Ikawa S, Nakada M, Eda K, Kagawa W, Takata M, Takeda S, Yokoyama S, Shibata T (May 2001). "Homologous-pairing activity of the human DNA-repair proteins Xrcc3.Rad51C". Proceedings of the National Academy of Sciences of the United States of America. 98 (10): 5538–43. doi:10.1073/pnas.091603098. PMC 33248. PMID 11331762.

Further reading

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