Gene: RAD51 was initially found to map to 15q15.1 (Shinohara A. et al., 1993). Further studies have shown that it is in the center of a region at chromosome 15q14-15 where a high frequency of loss of heterozygosity has been observed in human tumors (Schmutte C. et al., 1999). The gene consists of 10 exons and 9 introns and spans at least 30 kb. All exon-intron boundaries follow the GT-AC rule. The translation start codon is located in exon 2 and the average size of the coding exons is 112 bp. The noncoding exon 1 contains a CpG island that is approximately 990 bp in size. This putative promoter region contains several Sp1 recognition sites (consistent with the observed cell-cycle dependent expression of Rad51) but lacks a TATA box (Schmutte C. et al., 1999).
mRNA: size:
Protein: the RAD51 gene encodes a putative 339-amino acid protein homologue of the RecA protein of
Escherichia coli. Rad51 binds to single and double-stranded DNA and exhibits DNA-dependent ATPase activity to form nucleoprotein filaments, which have been observed under electron microscopy following negative staining (Benson F.E. et al., 1994). Specific interaction between Rad51 and
Rad52 has been demonstrated, suggesting that
Rad52 may modulate the catalytic activities of Rad51 protein, this interaction being species-specific (Shinohara A. et al., 1994; Shen Z. et al., 1996). Specific protein-protein associations between Rad51,
BRCA2 and p53 have been described;
BRCA2 inhibits p53 transcriptional activity in cancer cells and co-expression of Rad51 enhances
BRCA2's inhibitory effects (Marmorstein L.Y. et al., 1998). Interaction between Rad51 and
BRCA1 has been demonstrated through co-immunoprecipitate assays showing that the two proteins are located together in the cell nucleus of both ordinary cells and in cells undergoing meiosis (Scully R. et al., 1997).
Cell lines:
- No truncating mutations were found in
RAD51,
RAD52, and
RAD54, in 15 human breast cancer cell (BCC) lines (MDA-MB-157, -175-VI, -231, -415, -435, -436, -453, -468, MCF-7, MCF-7/Adr, UACC-893, T-47D, BT-483, -549, Hs578T (Bell D.W. et al., 1999).
Tumors:
- Loss of heterozygosity (LOH) was found in the RAD51 region in 31/98 (32%) breast tumors. LOH in this region was significantly correlated to
estrogen receptor negativity,
progesterone receptor negativity, higher histologic grade and higher stage (Gonzalez R. et al., 1999).
- In a series of 42 breast tumors, including 21 that clearly displayed LOH at chromosome 15q14-15, no alterations in the coding sequence of Rad51 were detected. It was therefore suggested that Rad51 is not the candidate tumor suppressor gene in tumors exhibiting a LOH at 15q14-15 (Schmutte C. et al., 1999).
-
RAD51,
RAD52, and
RAD54 were analysed for the presence of germ-line mutations in 100 cases with early-onset breast cancer. Two premature stop codons, ser346ter and Tyr415ter, were identified in germ-line
RAD52 alleles from 5% of early-onset breast cancer cases. Together, these two heterozygotous mutations were also found in 8% of a healthy control population, indicating that they do not confer an increased risk for breast cancer. A rare germ-line missense mutation was identified in
RAD54, whereas no sequence variants were found in
RAD51 (Bell D.W. et al., 1999).
Bell D.W. et al. (1999) Common nonsense mutations in
RAD52. Cancer Res. 59, 3883-3888.
Benson F.E. et al. (1994) Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA. EMBO J. 13, 5764-5771.
Gonzalez R. et al. (1999) Detection of loss of heterozygosity at RAD51,
RAD52,
RAD54 and
BRCA1 and
BRCA2 loci in breast cancer: pathological correlations. Br. J. Cancer 81, 503-509.
Marmorstein L.Y. et al. (1998) The
BRCA2 gene product functionally interacts with p53 and RAD51. Proc. Natl. Acad. Sci. USA 95, 13869-13874.
Schmutte C. et al. (1999) Characterization of the human Rad51 genomic locus and examination of tumors with 15q14-15 loss of heterozygosity (LOH). Cancer Res. 59, 4564-4569.
Scully R. et al. (1997) Association of
BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88, 265-275.
Shen Z. et al. (1996) Specific interaction between the human RAD51 and
RAD52 proteins. J. Biol. Chem. 271, 148-152.
Shinohara A. et al. (1993) Cloning of human, mouse and fission yeast recombination genes homologous to RAD51 and RecA. Nature Genet. 4, 239-243.
