RAD51D (RAD51-like 3 (S. cerevisiae))

2010-12-01   Mary K Taylor , Michael K Bedenbaugh , Susan M Brown , Brian D Yard , Douglas L Pittman 

South Carolina College of Pharmacy, University of South Carolina, Coker Life Sciences Building, 715 Sumter Street, Columbia, SC 29208, USA

Identity

HGNC
LOCATION
17q12
LOCUSID
ALIAS
BROVCA4,R51H3,RAD51L3,TRAD
FUSION GENES

DNA/RNA

Note

The human gene is composed of 10 exons. The study by Kawabata and Saeki (1999) describes alternative splicing of the human gene using a numbering scheme of 12 alternatively spliced exons. The exon alignment is illustrated below.
Further descriptions of mouse alternatively spliced variants are described in Gruver et al., 2009 and Kawabata et al., 2004.
Atlas Image
Human RAD51D alternative splicing. A. Exons 4 and 8 of the Kawabata and Saeki numbering scheme are considered "alternative exons" and not included in the reference sequence. B. Summary of splice variants and predicted translation products (for further details see the annexed document below).
Atlas Image
Annexe. RAD51L3 transcripts description.

Transcription

The HsTRAD transcript is the predominant variant. It is the full-length transcript and is made up of 2418 base pairs. This transcript will be used as the reference for the information that follows. There are multiple splice variants for the RAD51L3 gene that translate into one of seven putative protein isoforms.

Proteins

Note

The Saccharomyces cerevisiae Rad51 protein is homologous to the RecA protein of Escherichia coli. The RecA protein is known to promote repair via ATP-dependent mechanisms and is responsible for pairing and strand transfer between homologous DNA sequences. This is similar to the actions of the RAD51 protein in repair pathways. There are 5 members of the RAD51 family that share similar roles in recombination and DNA repair. RAD51D is one of these RecA-like genes (Pittman et al., 1998; Cartwright et al., 1998).
The RAD51D gene is predicted to encode seven different protein isoforms through alternative splicing. Isoform 1 is the predominant protein and is translated from the HsTRAD transcript mentioned previously (Kawabata and Saeki, 1999). The diagram below is based on this predominant form.
Atlas Image
RAD51L3 protein structure. Isoform 1 (from full-length transcript).

Description

The RAD51D protein contains regions necessary for interactions with other RAD51 paralogs as well as those that are required for proper function of the protein. RAD51D contains an ATP binding domain with highly conserved Walker A and B motifs (Pittman et al., 1998; Cartwright et al., 1998). Mutations targeting the conserved residues of glycine and lysine within the Walker A motif region resulted in a reduction in RAD51C binding ability and were shown to be required for DNA repair (Gruver et al., 2005). The Walker B motif contains a "GGQRE" sequence between residues 219-223 that is also required for DNA repair (Wiese et al., 2006). Furthermore, RAD51D-XRCC2 complex formation is significantly reduced with mutations targeting a highly conserved aspartate residue within the Walker B motif (Wiese et al., 2006).
A carboxyl terminal domain spanning amino acids 77-329 has been identified to be required for RAD51D to interact with RAD51C. In addition, the "linker region" located between residues 54-77 in the amino terminus is required for proper interactions with XRCC2. Together, these interactions aid in the repair of DNA damage (Miller et al., 2004; Gruver et al., 2009).

Expression

According to the study by Kawabata and Saeki (1999), RAD51L3 transcripts are expressed to varying degrees in the colon, prostate, spleen, testis, ovaries, thymus, small intestine and leukocytes.

Localisation

Located in the nucleus. Specifically, RAD51L3 localizes to the telomeres during both mitosis and meiosis (Tarsounas et al., 2004). There is evidence that RAD51L3 is found in the cytoplasm as well (Gruver et al., 2005).

Function

RAD51D is one of five members of the RAD51 gene family that is known to participate in repair of double stranded DNA breaks via homologous recombination. Without repair, the DNA damage can result in cell death or chromosomal aberrations that can ultimately lead to cancer (Thacker, 2005). Knockout studies with mice have shown a dramatic increase in levels of chromosomal aberrations, most notably, chromatid and chromosome breaks that occur through unrepaired replication forks (Smiraldo et al., 2005; Hinz et al., 2006). Proteomic studies have identified an interaction between RAD51D with the SFPQ protein (Rajesh et al., 2011). Exposure of mouse RAD51D-deficient cells to a strong alkylating agent results in G2/M cell cycle arrest and ultimately apoptosis (Rajesh et al., 2010). RAD51D has recently been shown to play a diverse role in cellular processes through its interaction with proteins involved in cell division, embryo development, protein and carbohydrate metabolism, cellular trafficking, protein synthesis, modification or folding, and cellular structure (Rajesh et al., 2009).
RAD51L3 is directly associated with telomeres prevents their dysfunction (Tarsounas et al., 2004). In mouse studies, RAD51L3 foci were present at telomeres in both meiosis and mitosis. Knockout studies showed that "RAD51D-deficient" mice exhibited an increase in end-to-end fusion and telomere attrition (Smiraldo et al., 2005). In addition, human studies using RAD51D-deficient cells have shown repeated shortening of the telomeric DNA, leading to chromosomal instability. This suggests a role for "RAD51D" in telomere capping. Failure to provide this function can lead to chromosomal aberrations (Tarsounas and West, 2005).

Homology

Canis lupus familiaris
[Dog]
Official gene name:
RAD51-like 3 (S. cerevisiae)
Genomic location:
chromosome 9
Reference material:

no primary references found

Pan troglodytes
[Chimpanzee]
Official gene name:
RAD51-like 3 (S. cerevisiae)
Genomic location:
chromosome 17
Reference material:

no primary references found

Bos taurus
[Cow]
Official gene name:
RAD51-like 3 (S. cerevisiae)
Genomic location:
chromosome 19
Reference material:

Zimin et al., 2009

Gallus gallus
[Chicken]
Official gene name:
RAD51-like 3 (S. cerevisiae)
Genomic location:
chromosome 19
Reference material:

no primary references found

Rattus norvegicus
[Rat]
Official gene name:
RAD51-like 3 (S. cerevisiae)
Genomic location:
chromosome 10
Reference material:

Strausberg et al., 2002

Mus musculus
[Mouse]
Official gene name:
RAD51-like 3 (S. cerevisiae)
Genomic location:
chromosome 11
Reference material:
Pittman et al., 1998
Cartwright et al., 1998
Arabidopsis thaliana
[Thale cress]
Official gene name:
RAD51D (ARABIDOPSIS HOMOLOG OF RAD51D)
Genomic location:
chromosome 1
Reference material:

Durrant et al., 2007

Oryza sativa
[Rice]

Official gene name:
Os09g0104200
Genomic location:
chromosome 9
**Hypothetical protein**
Reference material:

no primary references found

Danio rerio
[Zebrafish]
Official gene name:
zgc:77165
Genomic location:
chromosome 5
Reference material:

no primary references found

** Protein alignments and protein sequences are available at the HomoloGene database.

Mutations

Note

Single nucleotide polymorphisms have been identified in RAD51L3. However, only a small number of the major mutations occur in coding regions. The majority of the other mutations are present in various locations within the introns. Of the mutations affecting the gene, only one has an observed clinical association. It is observed that a mutation of the mRNA position 954 (SNP ID: rs28363284) results in an allele change to GGG (from the wild type GAG). This point mutation affects the 233rd amino acid as a glycine residue is observed in this particular mutation rather than the natural glutamic acid. This particular variation in amino acid sequence has been implicated as a precursor to breast cancer (see "Implicated In" section below). Another mutation observed in the coding region is at mRNA position 188 (SNP ID: rs1871892), resulting in a change in the sequence to TCA (from the wild type CCA). This particular substitution results in the insertion of proline at the 36th protein position rather than a serine. A third mutation observed is noted to occur at mRNA positions 810 (SNP ID: rs4796033). A mutation at this location results in a sequence of CAG (from the natural CGG). The effect of this substitution is the insertion of a glutamine residue at the 185th amino acid position rather than the arginine observed in the wild type gene. It is noted, that this particular mutation also occurs in 2 additional transcripts of the gene at the mRNA positions 750 and 414 affecting the 165th and 53rd amino acid residues respectively. Other mutations in the coding region include E237K (SNP ID: rs115031549), R252Q (SNP ID: rs28363283), A245T (SNP ID: rs28363282), A210T (SNP ID: rs80116829), E177D (SNP ID: rs55942401), and R24S (SNP ID: rs28363257).

Implicated in

Entity name
Cancer
Disease
Cancer arises in part due to the accumulation of genetic damage. Furthermore, such damage has a greater tendency to be found in significant levels when genetic repair pathways such as DNA mismatch repair and homologous recombination (HR) are defective. Involved in the pathway of HR are numerous proteins that are known as the RAD51 paralogs (RAD51L1, RAD51L2, RAD51L3, XRCC2 and XRCC3). It is believed that the lack of genetic stability created from the loss of this pathway, HR, is significant in initiation and potentially the progression of cancer. In particular, defects in the HR pathway have been noted to be associated with breast and ovarian cancer (Thacker, 2005); however, it is plausible that such a defect could potentially lead to multiple forms of cancer due to the accumulation of genetic mutations (although it takes significant damage accumulation to lead to tumor formation). A RAD51L3 variant does have an association with increased familial breast cancer risk (Rodríguez-López et al., 2004).
Entity name
Breast cancer
Note
Although conflicting data exist, the RAD51D-E233G variant allele has been identified as a potential precursor to breast cancers in women with high familial risk but do not possess a BRCA1/BRCA2 mutation (Rodríguez-López et al., 2004; Dowty et al., 2008).
Disease
In an initial study that screened for possible breast cancer alleles, it was determined that the exon 8 mutation led to an increased frequency of breast cancer in a specific group of cases (familial cancer cases) versus the control group (Rodríguez-López et al., 2004). Additionally, individuals expressing the RAD51D-E233G variant have been shown to have higher proliferative indices and a less favorable clinical immunohistochemical pattern (Rodríguez-López et al., 2004). However, another study found no statistically significant evidence that this variant is associated with breast cancer risk. Yet, this study did find that it was plausible that the variable could lead to a small increase in the risk of breast cancer and that a small, yet insignificant, effect was made by the variant on the risk of breast cancer (approximately 30%) (Dowty et al., 2008).
Prognosis
It has been noted that the RAD51D-E223G variant confers increased resistance to DNA damaging agents such as: mitomycin C, cisplatin, ultraviolet light, and methyl methane sulfonate, and taxol. This presents clinical implications as these are commonly utilized therapies. Furthermore, the variant has increased cellular proliferation and telomere maintenance compared to the wild-type and exhibits reduced interaction with the binding partner RAD51C but does not affect binding to XRCC2 (Nadkarni et al., 2009b).
Entity name
Blooms syndrome
Disease
Blooms syndrome is an autosomal recessive disorder of rare occurrence. Characteristics include short stature, immunodeficiency, fertility defects, and increased risk for the development of various types of cancer. Cells associated with this disorder are noted for their genomic instability. They exhibit an increase in sister chromatid and homologous chromosome exchanges. In normal, healthy cells, BLM, a helicase of the RecQ family, interacts with the RAD51L3 portion of the RAD51L3-XRCC2 heteromeric complex. Upon joining with the complex, BLM disrupts synthetic 4-way junctions that resemble Holliday junctions suggesting an important role for the protein-protein interaction in DNA repair. The mutated form of the gene encoding for this protein, which occurs in Blooms syndrome, results in the inability for BLM to bind to RAD51L3. Absence of normal BLM function leads to the characteristic elevation in recombination events seen in Blooms syndrome (Braybrooke et al., 2003).

Bibliography

Pubmed IDLast YearTitleAuthors
129753632003Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D).Braybrooke JP et al
95125351998Isolation of novel human and mouse genes of the recA/RAD51 recombination-repair gene family.Cartwright R et al
180582262008The RAD51D E233G variant and breast cancer risk: population-based and clinic-based family studies of Australian women.Dowty JG et al
173605042007Arabidopsis SNI1 and RAD51D regulate both gene transcription and DNA recombination during the defense response.Durrant WE et al
162367632005The ATPase motif in RAD51D is required for resistance to DNA interstrand crosslinking agents and interaction with RAD51C.Gruver AM et al
193271482009Functional characterization and identification of mouse Rad51d splice variants.Gruver AM et al
165226462006Repression of mutagenesis by Rad51D-mediated homologous recombination.Hinz JM et al
152971442004Genomic structure and multiple alternative transcripts of the mouse TRAD/RAD51L3/RAD51D gene, a member of the recA/RAD51 gene family.Kawabata M et al
117516352001Identification and purification of two distinct complexes containing the five RAD51 paralogs.Masson JY et al
147043542004Domain mapping of the Rad51 paralog protein complexes.Miller KA et al
193478802009Cisplatin resistance conferred by the RAD51D (E233G) genetic variant is dependent upon p53 status in human breast carcinoma cell lines.Nadkarni A et al
95709541998Identification, characterization, and genetic mapping of Rad51d, a new mouse and human RAD51/RecA-related gene.Pittman DL et al
208137592011The splicing-factor related protein SFPQ/PSF interacts with RAD51D and is necessary for homology-directed repair and sister chromatid cohesion.Rajesh C et al
196581022009The interaction profile of homologous recombination repair proteins RAD51C, RAD51D and XRCC2 as determined by proteomic analysis.Rajesh C et al
201332102010RAD51D protects against MLH1-dependent cytotoxic responses to O(6)-methylguanine.Rajesh P et al
151706662004The variant E233G of the RAD51D gene could be a low-penetrance allele in high-risk breast cancer families without BRCA1/2 mutations.Rodríguez-López R et al
151620122004Recombination repair pathway in the maintenance of chromosomal integrity against DNA interstrand crosslinks.Sasaki MS et al
107498672000Evidence for simultaneous protein interactions between human Rad51 paralogs.Schild D et al
157816182005Extensive chromosomal instability in Rad51d-deficient mouse cells.Smiraldo PG et al
124779322002Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.Strausberg RL et al
158461032005Recombination at mammalian telomeres: an alternative mechanism for telomere protection and elongation.Tarsounas M et al
157237112005The RAD51 gene family, genetic instability and cancer.Thacker J et al
167172882006Disparate requirements for the Walker A and B ATPase motifs of human RAD51D in homologous recombination.Wiese C et al
193930382009A whole-genome assembly of the domestic cow, Bos taurus.Zimin AV et al

Other Information

Locus ID:

NCBI: 5892
MIM: 602954
HGNC: 9823
Ensembl: ENSG00000185379

Variants:

dbSNP: 5892
ClinVar: 5892
TCGA: ENSG00000185379
COSMIC: RAD51D

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000185379ENST00000335858O75771
ENSG00000185379ENST00000345365O75771
ENSG00000185379ENST00000394589O75771
ENSG00000185379ENST00000460118H0UID0
ENSG00000185379ENST00000585343K7ESI1
ENSG00000185379ENST00000586044O75771
ENSG00000185379ENST00000586186K7ERM7
ENSG00000185379ENST00000586210K7EKG7
ENSG00000185379ENST00000587405K7EMF1
ENSG00000185379ENST00000587977O75771
ENSG00000185379ENST00000588372K7ESL4
ENSG00000185379ENST00000588594O75771
ENSG00000185379ENST00000590016O75771
ENSG00000185379ENST00000590631K7EJ58
ENSG00000185379ENST00000592577K7EN92
ENSG00000185379ENST00000592850K7ESI1

Expression (GTEx)

0
1
2
3
4
5
6
7
8
9

Pathways

PathwaySourceExternal ID
Homologous recombinationKEGGko03440
Homologous recombinationKEGGhsa03440
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
DNA RepairREACTOMER-HSA-73894
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
Resolution of D-Loop StructuresREACTOMER-HSA-5693537
Resolution of D-loop Structures through Holliday Junction IntermediatesREACTOMER-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)REACTOMER-HSA-5693554
TP53 Regulates Transcription of DNA Repair GenesREACTOMER-HSA-6796648

References

Pubmed IDYearTitleCitations
218222672011Germline mutations in RAD51D confer susceptibility to ovarian cancer.155
284184442017Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer.109
151094942004Telomere maintenance requires the RAD51D recombination/repair protein.74
262612512015Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.64
240887862013Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity.40
129753632003Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D).31
118347242002Homologous pairing and ring and filament structure formation activities of the human Xrcc2*Rad51D complex.27
208197782010MicroRNA-related genetic variations as predictors for risk of second primary tumor and/or recurrence in patients with early-stage head and neck cancer.21
226525332012A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer.20
167172882006Disparate requirements for the Walker A and B ATPase motifs of human RAD51D in homologous recombination.16

Citation

Mary K Taylor ; Michael K Bedenbaugh ; Susan M Brown ; Brian D Yard ; Douglas L Pittman

RAD51D (RAD51-like 3 (S. cerevisiae))

Atlas Genet Cytogenet Oncol Haematol. 2010-12-01

Online version: http://atlasgeneticsoncology.org/gene/347/rad51d-(rad51-like-3-(s-cerevisiae))