RAD52 (RAD52 homolog (S. cerevisiae))

2014-02-01   Benjamin H Lok , Simon N Powell 

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

Identity

HGNC
LOCATION
12p13.33
LOCUSID
ALIAS
-
FUSION GENES

DNA/RNA

Note

The human and murine RAD52 gene is composed of 12 exons. Kito et al. identified three RAD52 isoforms designated RAD52β (226 amino acids), RAD52γ (139 amino acids), and RAD52δ (118 amino acids) which were able to bind ssDNA and dsDNA much like reference RAD52 (RAD52α). However, these isoforms lacked the ability to associate with RAD52α (Kito et al., 1999).
Thorpe and colleagues describe two splice variants that conferred increased homology-directed repair in the murine RAD52 gene RAD52Δexon4 and RAD52+intron8 (Thorpe et al., 2006).
Atlas Image

Proteins

Note

The human RAD52 (hRAD52) protein is similar to the Saccharomyces cerevisiae RAD52 protein (ScRAD52) both structurally and biochemically. However the phenotypic properties of RAD52, particularly in mediating homologous recombination varies amongst the evolutionary spectrum.
Atlas Image
Secondary structure of the hRAD52 protein. From Uniprot.org (Creative Commons License).

Description

hRAD52 protein is comprised of 418 amino acids and forms a heptameric ring (Stasiak et al., 2000), which is mediated by the N-terminus (Ranatunga et al., 2001). This N-terminal portion binds ssDNA (Mortensen et al., 1996).
The well-studied hRAD521-212 is the N-terminal portion which forms an undecameric ringed polymer (Kagawa et al., 2002). DNA binding properties are linked to various amino acids, including, Arg-55, Tyr-65, Lys-152, Arg-153, Arg-156. Arg-55 and Lys-152 are necessarily for ssDNA binding, whereas Tyr-65, Arg-152, and Arg-156 are essential for binding both ssDNA and dsDNA (Kagawa et al., 2002). Phe-79 and Lys-102 have also shown a role in ssDNA and dsDNA binding, respectively (Lloyd et al., 2005). Interfering with the Phe-79 of hRAD52 was recently demonstrated to disrupt the RAD52-DNA interaction leading to an accumulation of DNA double-strand breaks (DSBs) particularly in BRCA1/2 deficient cells (Cramer-Morales et al., 2013). Further study is required to decipher the hierarchy of these respective sites and study additional novel binding sites.
Please see the following diagram for the location of several of these amino acid sites.
Atlas Image
Secondary structure of the hRAD52 protein. From Kagawa et al. 2002, with permission from Elsevier.
Atlas Image
The hRAD521-212 undecameric polymer with principal DNA binding amino acid residues labeled residing in the predominantly positively charged groove. From Kagawa et al. 2002, with permission from Elsevier.

Localisation

ScRAD52 is a nuclear protein and predominantly recruited into sub-nuclear foci during the S-phase of the cell cycle (Lisby et al., 2001). hRAD52 sub-nuclear foci formation after exposure to ionizing radiation is dependent on c-Abl-mediated phosphorylation (Kitao and Yuan, 2002).

Function

ScRAD52 mediates RAD51 recombination activity and thus homology-directed repair (Milne and Weaver, 1993). hRAD52 also demonstrates this ability to stimulate homologous pairing by hRAD51 (Benson et al., 1998). The interaction of ScRAD52 and hRAD52 with replication protein A (RPA) is important for the binding with ssDNA by RAD52 (Hays et al., 1998; Shinohara et al., 1998; Jackson et al., 2002). hRAD52 binds directly to DSBs, protects them from exonuclease resection, and facilitates end-to-end interaction (Van Dyck et al., 1999). Furthermore, capture of the second DNA end in homologous recombination appears to involve RAD52-mediated annealing of RPA-ssDNA strands in biochemical reactions (Sugiyama et al., 2006).
Although, ScRAD52 and hRAD52 does not stimulate RAD51 DNA strand exchange with RPA-ssDNA complexes in biochemical assays (Jensen et al., 2010), under certain conditions, hRAD52 does promote RAD51-mediated homologous DNA pairing (Baumann and West, 1999).
hRAD52 mediates RAD51 recombination function in human cancer cells deficient in BRCA1 (Cramer-Morales et al., 2013; Lok et al., 2013), PALB2 (Lok et al., 2013) or BRCA2 (Feng et al., 2011). RAD52 is able to mediate RAD51-mediated homology-directed repair when the predominant BRCA1-PALB2-BRCA2 homologous recombination pathway is perturbed (see figure below). The RAD52-RAD51 pathway also appears to function independently of the RAD51 paralogs RAD51B/RAD51C/RAD51D-XRCC2 (Chun et al., 2013).
ScRAD52 is required for RAD51-independent single-strand annealing (SSA) (Singleton et al., 2002; Symington, 2002) and break-induced replication (BIR) (Malkova et al., 1996; Ira and Haber, 2002; McEachern and Haber, 2006).
Atlas Image
The BRCA and RAD52 pathways of DNA double-strand break repair. *There is currently no well-defined evidence that single-end DSBs or daughter-strand gaps are repaired by single strand annealing. From Lok and Powell, 2012.
Atlas Image
Modified from HomoloGene.

Mutations

Note

Currently, there are no known mutations of RAD52 that lead to human disease, including none associated with breast cancer (Bell et al., 1999), ovarian cancer (Tong et al., 2003; Beesley et al., 2007) or chronic lymphocytic leukemia (Sellick et al., 2008).

Implicated in

Entity name
Resistance to platinum-based chemotherapy
Prognosis
There is a report of uncertain significance by Shi et al. that may link certain RAD52 variants and RAD52 protein expression levels to resistance to platinum-based chemotherapy (Shi et al., 2012), however no other published studies have demonstrated a similar association.

Bibliography

Pubmed IDLast YearTitleAuthors
104386261999Heteroduplex formation by human Rad51 protein: effects of DNA end-structure, hRP-A and hRad52.Baumann P et al
180867582007Association between single-nucleotide polymorphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: results from two Australian studies and an additional validation set.Beesley J et al
104635751999Common nonsense mutations in RAD52.Bell DW et al
94507581998Synergistic actions of Rad51 and Rad52 in recombination and DNA repair.Benson FE et al
231499362013Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway.Chun J et al
238365602013Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.Cramer-Morales K et al
211481022011Rad52 inactivation is synthetically lethal with BRCA2 deficiency.Feng Z et al
96328241998Studies of the interaction between Rad52 protein and the yeast single-stranded DNA binding protein RPA.Hays SL et al
121920382002Characterization of RAD51-independent break-induced replication that acts preferentially with short homologous sequences.Ira G et al
121399392002Analysis of the human replication protein A:Rad52 complex: evidence for crosstalk between RPA32, RPA70, Rad52 and DNA.Jackson D et al
207298322010Purified human BRCA2 stimulates RAD51-mediated recombination.Jensen RB et al
121914812002Crystal structure of the homologous-pairing domain from the human Rad52 recombinase in the undecameric form.Kagawa W et al
123796502002Regulation of ionizing radiation-induced Rad52 nuclear foci formation by c-Abl-mediated phosphorylation.Kitao H et al
106730311999Identification of novel isoforms of human RAD52.Kito K et al
114599642001Rad52 forms DNA repair and recombination centers during S phase.Lisby M et al
155717182005Identification of residues important for DNA binding in the full-length human Rad52 protein.Lloyd JA et al
229646432013RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination.Lok BH et al
230712612012Molecular pathways: understanding the role of Rad52 in homologous recombination for therapeutic advancement.Lok BH et al
86929571996Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication.Malkova A et al
167564872006Break-induced replication and recombinational telomere elongation in yeast.McEachern MJ et al
83705241993Dominant negative alleles of RAD52 reveal a DNA repair/recombination complex including Rad51 and Rad52.Milne GT et al
88552481996DNA strand annealing is promoted by the yeast Rad52 protein.Mortensen UH et al
112789782001Human RAD52 exhibits two modes of self-association.Ranatunga W et al
182030222008Germline mutations in RAD51, RAD51AP1, RAD51B, RAD51C,RAD51D, RAD52 and RAD54L do not contribute to familial chronic lymphocytic leukemia.Sellick G et al
232097462012RAD52 variants predict platinum resistance and prognosis of cervical cancer.Shi TY et al
96196271998Rad52 forms ring structures and co-operates with RPA in single-strand DNA annealing.Shinohara A et al
123704102002Structure of the single-strand annealing domain of human RAD52 protein.Singleton MR et al
107449772000The human Rad52 protein exists as a heptameric ring.Stasiak AZ et al
170935002006Rad52-mediated DNA annealing after Rad51-mediated DNA strand exchange promotes second ssDNA capture.Sugiyama T et al
124567862002Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair.Symington LS et al
166484712006Cells expressing murine RAD52 splice variants favor sister chromatid repair.Thorpe PH et al
128837402003Rad52 gene mutations in breast/ovarian cancer families and sporadic ovarian carcinoma patients.Tong D et al
102272971999Binding of double-strand breaks in DNA by human Rad52 protein.Van Dyck E et al

Other Information

Locus ID:

NCBI: 5893
MIM: 600392
HGNC: 9824
Ensembl: ENSG00000002016

Variants:

dbSNP: 5893
ClinVar: 5893
TCGA: ENSG00000002016
COSMIC: RAD52

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000002016ENST00000358495P43351
ENSG00000002016ENST00000358495Q5DR82
ENSG00000002016ENST00000397230E9PF95
ENSG00000002016ENST00000430095P43351
ENSG00000002016ENST00000430095Q5DR82
ENSG00000002016ENST00000461568P43351
ENSG00000002016ENST00000468231P43351
ENSG00000002016ENST00000536177F5GX32
ENSG00000002016ENST00000541619P43351
ENSG00000002016ENST00000542785F5GX95
ENSG00000002016ENST00000543912F5H1K5
ENSG00000002016ENST00000544742P43351
ENSG00000002016ENST00000545564P43351

Expression (GTEx)

0
5
10
15
20
25

Pathways

PathwaySourceExternal ID
Homologous recombinationKEGGko03440
Homologous recombinationKEGGhsa03440
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
SUMOylation of DNA damage response and repair proteinsREACTOMER-HSA-3108214
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 Single Strand Annealing (SSA)REACTOMER-HSA-5685938

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA445204Ovarian NeoplasmsDiseaseClinicalAnnotationassociatedPD24533712
PA449014cisplatinChemicalClinicalAnnotationassociatedPD24533712
PA449165cyclophosphamideChemicalClinicalAnnotationassociatedPD24533712

References

Pubmed IDYearTitleCitations
211481022011Rad52 inactivation is synthetically lethal with BRCA2 deficiency.133
123704102002Structure of the single-strand annealing domain of human RAD52 protein.99
121914812002Crystal structure of the homologous-pairing domain from the human Rad52 recombinase in the undecameric form.95
279847452016RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress.88
229646432013RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination.78
120239822002Variants in DNA double-strand break repair genes and breast cancer susceptibility.74
200812072010Human Rad52 binds and wraps single-stranded DNA and mediates annealing via two hRad52-ssDNA complexes.61
183133882008DNA repair synthesis facilitates RAD52-mediated second-end capture during DSB repair.55
238365602013Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.54
120369132002Effect of germ-line genetic variation on breast cancer survival in a population-based study.49

Citation

Benjamin H Lok ; Simon N Powell

RAD52 (RAD52 homolog (S. cerevisiae))

Atlas Genet Cytogenet Oncol Haematol. 2014-02-01

Online version: http://atlasgeneticsoncology.org/gene/349/rad52