Biology:RAD51C

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5889. 
  2. ↑ "Isolation and characterization of RAD51C, a new human member of the RAD51 family of related genes". Nucleic Acids Research 26 (5): 1179–84. March 1998. doi:10.1093/nar/26.5.1179. PMID 9469824. 
  3. ↑ "Domain mapping of the Rad51 paralog protein complexes". Nucleic Acids Research 32 (1): 169–78. 2004. doi:10.1093/nar/gkg925. PMID 14704354. 
  4. ↑ 4.0 4.1 4.2 4.3 "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. January 2013. doi:10.1128/MCB.00465-12. PMID 23149936. 
  5. ↑ "17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes". Cancer Research 60 (19): 5371–5. October 2000. PMID 11034073. 
  6. ↑ Wade N (2008-12-25). "The Chaos Inside a Cancer Cell". Science Visuals. NYTimes.com. https://www.nytimes.com/2008/12/25/science/25visual.html. 
  7. ↑ 7.0 7.1 "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. February 2009. doi:10.1101/gr.080259.108. PMID 19056696. 
  8. ↑ "Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene". Nature Genetics 42 (5): 410–4. May 2010. doi:10.1038/ng.569. PMID 20400964. 
  9. ↑ "RAD51C germline mutations in breast and ovarian cancer cases from high-risk families". PLOS ONE 6 (9): e25632. 2011. doi:10.1371/journal.pone.0025632. PMID 21980511. Bibcode: 2011PLoSO...625632C. 
  10. ↑ "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. January 2016. doi:10.1007/s10549-015-3674-y. PMID 26740214. 
  11. ↑ "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. September 2015. doi:10.1200/JCO.2015.61.2408. PMID 26261251. 
  12. ↑ "Genetic testing for RAD51C mutations: in the clinic and community". Clinical Genetics 88 (4): 303–12. October 2015. doi:10.1111/cge.12548. PMID 25470109. 
  13. ↑ 13.0 13.1 "Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status". Scientific Reports 4: 4026. February 2014. doi:10.1038/srep04026. PMID 24504028. Bibcode: 2014NatSR...4E4026C. 
  14. ↑ "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. February 2014. doi:10.1158/1078-0432.CCR-13-2287. PMID 24240112. 
  15. ↑ "Current and future role of genetic screening in gynecologic malignancies". American Journal of Obstetrics and Gynecology 217 (5): 512–521. November 2017. doi:10.1016/j.ajog.2017.04.011. PMID 28411145. 
  16. ↑ 16.0 16.1 "Overexpression of Rad51C splice variants in colorectal tumors". Oncotarget 6 (11): 8777–87. April 2015. doi:10.18632/oncotarget.3209. PMID 25669972. 
  17. ↑ "RAD51C-deficient cancer cells are highly sensitive to the PARP inhibitor olaparib". Molecular Cancer Therapeutics 12 (6): 865–77. June 2013. doi:10.1158/1535-7163.MCT-12-0950. PMID 23512992. 
  18. ↑ "The role of EZH2 in tumour progression". British Journal of Cancer 106 (2): 243–7. January 2012. doi:10.1038/bjc.2011.551. PMID 22187039. 
  19. ↑ 19.0 19.1 "Diverse involvement of EZH2 in cancer epigenetics". American Journal of Translational Research 7 (2): 175–93. 2015. PMID 25901190. 
  20. ↑ "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. September 2003. doi:10.1073/pnas.1933744100. PMID 14500907. Bibcode: 2003PNAS..10011606K. 
  21. ↑ "The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells". Neoplasia 7 (11): 1011–9. November 2005. doi:10.1593/neo.05472. PMID 16331887. 
  22. ↑ "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. September 2006. doi:10.1007/s10735-006-9042-9. PMID 16855786. 
  23. ↑ 23.0 23.1 "Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways". Human Molecular Genetics 13 (12): 1241–8. June 2004. doi:10.1093/hmg/ddh135. PMID 15115758. 
  24. ↑ 24.0 24.1 24.2 24.3 "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. March 2002. doi:10.1074/jbc.M108306200. PMID 11744692. 
  25. ↑ "Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange". Genes & Development 15 (24): 3308–18. December 2001. doi:10.1101/gad.935501. PMID 11751636. 
  26. ↑ 26.0 26.1 26.2 "Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells". Nucleic Acids Research 30 (4): 1009–15. February 2002. doi:10.1093/nar/30.4.1009. PMID 11842113. 
  27. ↑ "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. May 2001. doi:10.1073/pnas.091603098. PMID 11331762. 

Further reading




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