RAD51C

RAD51C
Identifiers
Aliases	RAD51C, BROVCA3, FANCO, R51H3, RAD51L2, RAD51 paralog C
External IDs	MGI: 2150020 HomoloGene: 14238 GeneCards: RAD51C
Gene ontology Molecular function • crossover junction endodeoxyribonuclease activity • DNA binding • nucleotide binding • DNA-dependent ATPase activity • recombinase activity • single-stranded DNA binding • protein binding • four-way junction DNA binding • double-stranded DNA binding • ATP binding Cellular component • cytoplasm • replication fork • nucleoplasm • condensed nuclear chromosome • Rad51C-XRCC3 complex • mitochondrion • perinuclear region of cytoplasm • Rad51B-Rad51C-Rad51D-XRCC2 complex • Holliday junction resolvase complex • nucleus Biological process • strand invasion • response to ionizing radiation • DNA recombinase assembly • reciprocal meiotic recombination • DNA recombination • male meiosis I • blood coagulation • female meiosis sister chromatid cohesion • sister chromatid cohesion • cellular response to DNA damage stimulus • telomere maintenance via recombination • spermatogenesis • positive regulation of G2/M transition of mitotic cell cycle • chromosome organization involved in meiotic cell cycle • mitotic recombination • DNA repair • DNA synthesis involved in DNA repair • double-strand break repair via homologous recombination • strand displacement Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5889	114714
Ensembl	ENSG00000108384	ENSMUSG00000007646
UniProt	O43502	Q924H5
RefSeq (mRNA)	NM_002876 NM_058216	NM_001291440 NM_053269
RefSeq (protein)	NP_002867.1 NP_478123.1	NP_001278369.1 NP_444499.1
Location (UCSC)	Chr 17: 58.69 – 58.74 Mb	Chr 11: 87.38 – 87.4 Mb
PubMed search	[1]	[2]
Wikidata

RAD51 homolog C (S. cerevisiae), also known as RAD51C, is a protein which in humans is encoded by the RAD51C gene.^[3][4]

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.^[5]

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.^[6]

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.^[6] 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.^[6] The CX3 complex was shown to associate with Holliday junction resolvase activity, probably in a role of stabilizing gene conversion tracts.^[6]

The RAD51C gene is one of genes four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors.^[7] 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.^[3]

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.^[8][9] Since the RAD51C protein is involved in repairing double strand chromosome breaks, this chromosomal rearrangement could be responsible for the other rearrangements.^[9]

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.^[10][11][12] 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.^[13] 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 9%.^[14][15][16]

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.^[17] 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^[17]

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.^[18] On the other hand, methylation of the RAD51C promoter was only found in about 1.5% of ovarian cancer cases.^[15]

EZH2 protein is up-regulated in numerous cancers.^[19][20] 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.^[21] 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.^[20] EZH2 targets RAD51C, reducing RAD51C mRNA and protein expression (and also represses other RAD51 paralogs RAD51B, RAD51D, XRCC2 and XRCC3).^[22] Increased expression of EZH2, leading to repression of RAD51 paralogs and consequent reduced homologous recombinational repair, was proposed as a cause of breast cancer.^[23]

Interactions

RAD51C has been shown to interact with:

• RAD51L1,^[24][25][26]
• RAD51L3,^[25][27] and
• XRCC2,^[25][27] and
• XRCC3.^{[24][25][27][28]}

References

Further reading