RAD52
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Location (UCSC) | Chr 12: 0.91 – 0.99 Mb | Chr 6: 119.88 – 119.9 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
RAD52 homolog (S. cerevisiae), also known as RAD52, is a protein which in humans is encoded by the RAD52 gene.[5][6]
Function
The protein encoded by this gene shares similarity with Saccharomyces cerevisiae Rad52, a protein important for DNA double-strand break repair and homologous recombination. This gene product was shown to bind single-stranded DNA ends, and mediate the DNA-DNA interaction necessary for the annealing of complementary DNA strands. It was also found to interact with DNA recombination protein RAD51, which suggested its role in RAD51-related DNA recombination and repair.[6]
Role in DNA recombination repair
RAD52 mediates RAD51 function in homologous recombinational repair (HRR) in both yeast Saccharomyces cerevisiae and in mammalian cells of mice and humans. However, the RAD52 protein has distinctly different functions in HRR of yeast and humans. In S. cerevisiae, Rad52 protein, acting alone, facilitates the loading of Rad51 protein onto single-stranded DNA pre-coated with replication protein A in the presynaptic phase of recombination.[7][8]
In mice and humans, however, BRCA2 primarily mediates orderly assembly of RAD51 on ssDNA, the form that is active for homologous pairing and strand invasion.[9] BRCA2 also redirects RAD51 from dsDNA and prevents dissociation from ssDNA.[9] In addition, the four paralogs of RAD51, consisting of RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 form a complex called the BCDX2 complex. This complex participates in RAD51 recruitment or stabilization at damage sites.[10] The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament. However, in the presence of a BRCA2 mutation, human RAD52 can mediate RAD51 assembly on ssDNA and substitute for BRCA2 in homologous recombinational DNA repair,[11] though with lower efficiency than BRCA2.
In addition, human RAD52, in combination with ERCC1, promotes the error-prone homologous DNA repair pathway of single-strand annealing.[12] Though error prone, this repair pathway may be needed for survival of cells with DNA damage that is not otherwise repairable.
Human RAD52 also has an important role in repair of DNA double-strand breaks at active transcription sites during the G0/G1 phase of the cell cycle. Repair of these double-strand breaks appears to use an RNA template-based recombination mechanism dependent on RAD52.[13] The Cockayne Syndrome B protein (CSB) (coded for by ERCC6) localizes at double-strand breaks at sites of active transcription, followed by RAD51, RAD51C and RAD52 to carry out homologous recombinational repair using the newly synthesized RNA as a template.[13]
microRNAs and cancer risk
Three prime untranslated regions (3'UTRs) of messenger RNAs (mRNAs) often contain regulatory sequences that can cause post-transcriptional RNA silencing. Such 3'-UTRs often contain binding sites for microRNAs (miRNAs). By binding to specific sites within the 3'-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript.
MicroRNAs (miRNAs) appear to regulate the expression of more than 60% of protein coding genes of the human genome.[14] One microRNA, miR-210, represses RAD52.[15] As noted by Devlin et al., miR-210 is up-regulated in most solid tumors and negatively affects the clinical outcome.[16]
The 3'-UTR of RAD52 also has a binding site for the microRNA let-7. Women with a single-nucleotide polymorphism (SNP) in the binding site for let-7 (rs7963551), that causes reduced binding of let-7, likely have increased expression of RAD52 (as was shown for this SNP in liver[17]). Women with this SNP in the 3'UTR of RAD52 showed a reduced breast cancer risk with an odds ratio of 0.84, 95% confidence interval of 0.75-0.95.[18]
In a Han Chinese population, the same SNP as above in the 3'-UTR of RAD52 binding site for let-7 (rs7963551) reduced the risk of glioma. The risk of glioma associated with the RAD52 rs7963551 genotype had an odds ratio (compared to those without the SNP) of 0.44 for those older than 41 years, and an odds ratio of 0.58 for those 41 years or younger.[19]
Li et al.[17] found significantly decreased hepatic cellular carcinoma risk among individuals with the RAD52 rs7963551 CC genotype (the same SNP as above) compared with those with the AA genotype in a Chinese population. They also found that in 44 normal human liver tissue samples, presence of the rs7963551 SNP was associated with a significant increase of RAD52 mRNA expression.
Thus increased RAD52 expression is protective against various cancers.
Another study of altered microRNA binding sites in RAD52 and their effects on cancer susceptibility was carried out by Naccarati et al.[20] They found two RAD52 microRNA binding sites that were frequently altered and had an effect on colon cancer risk. Individuals with a homozygous or heterozygous SNP in rs1051669 were at increased risk of colon cancer (OR 1.78, 95% CI 1.13–2.80, p = 0.01 for homozygotes and OR 1.72, 95% CI 1.10–2.692, p = 0.02 for heterozygotes). Heterozygous carriers of the other RAD52 SNP (rs11571475) were at decreased risk of colon cancer (OR 0.76, 95% CI 0.58–1.00, p = 0.05). Of 21 genes in the homologous recombinational repair pathway and 7 genes in the non-homologous end joining pathway examined, the only SNPs found in microRNA binding regions which were both at high enough frequency to evaluate and which affected risks of colon cancer, were the two in RAD52 and one in MRE11A.
DNA damage appears to be the primary underlying cause of cancer,
Interactions
RAD52 has been shown to
Intragenic complementation
When multiple copies of a polypeptide encoded by a
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000002016 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030166 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- .
- ^ a b EntrezGene 5893 aka RAD52 homolog, DNA repair protein [''Homo sapiens'' (human)]
- S2CID 4304549.
- S2CID 4408959.
- ^ PMID 21731065.
- PMID 23149936.
- PMID 21148102.
- PMID 15485900.
- ^ PMID 26100862.
- PMID 18955434.
- PMID 19141645.
- PMID 21360638.
- ^ S2CID 25174260.
- PMID 23188672.
- S2CID 1082923.
- PMID 26735576.
- PMID 18403632.
- PMID 18082599.
- PMID 18704159.
- PMID 17616978.
- S2CID 2587580.
- ^ Boundy-Mills KL, Livingston DM. A Saccharomyces cerevisiae RAD52 allele expressing a C-terminal truncation protein: activities and intragenic complementation of missense mutations. Genetics. 1993;133(1):39-49.
Further reading
- Muris DF, Bezzubova O, Buerstedde JM, Vreeken K, Balajee AS, Osgood CJ, Troelstra C, Hoeijmakers JH, Ostermann K, Schmidt H (Nov 1994). "Cloning of human and mouse genes homologous to RAD52, a yeast gene involved in DNA repair and recombination". Mutation Research. 315 (3): 295–305. PMID 7526206.
- Shen Z, Denison K, Lobb R, Gatewood JM, Chen DJ (Jan 1995). "The human and mouse homologs of the yeast RAD52 gene: cDNA cloning, sequence analysis, assignment to human chromosome 12p12.2-p13, and mRNA expression in mouse tissues". Genomics. 25 (1): 199–206. PMID 7774919.
- Park MS (Jun 1995). "Expression of human RAD52 confers resistance to ionizing radiation in mammalian cells". The Journal of Biological Chemistry. 270 (26): 15467–70. PMID 7797537.
- Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ (Sep 1996). "UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins". Genomics. 36 (2): 271–9. PMID 8812453.
- Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ (Oct 1996). "Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system". Genomics. 37 (2): 183–6. PMID 8921390.
- Chen G, Yuan SS, Liu W, Xu Y, Trujillo K, Song B, Cong F, Goff SP, Wu Y, Arlinghaus R, Baltimore D, Gasser PJ, Park MS, Sung P, Lee EY (Apr 1999). "Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl" (PDF). The Journal of Biological Chemistry. 274 (18): 12748–52. S2CID 2587580.
- Kito K, Wada H, Yeh ET, Kamitani T (Dec 1999). "Identification of novel isoforms of human RAD52". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1489 (2–3): 303–14. PMID 10673031.
- Stasiak AZ, Larquet E, Stasiak A, Müller S, Engel A, Van Dyck E, West SC, Egelman EH (Mar 2000). "The human Rad52 protein exists as a heptameric ring". Current Biology. 10 (6): 337–40. S2CID 16087838.
- Parsons CA, Baumann P, Van Dyck E, West SC (Aug 2000). "Precise binding of single-stranded DNA termini by human RAD52 protein". The EMBO Journal. 19 (15): 4175–81. PMID 10921897.
- Mer G, Bochkarev A, Gupta R, Bochkareva E, Frappier L, Ingles CJ, Edwards AM, Chazin WJ (Oct 2000). "Structural basis for the recognition of DNA repair proteins UNG2, XPA, and RAD52 by replication factor RPA". Cell. 103 (3): 449–56. S2CID 16640087.
- Ranatunga W, Jackson D, Flowers II RA, Borgstahl GE (Jul 2001). "Human RAD52 protein has extreme thermal stability". Biochemistry. 40 (29): 8557–62. PMID 11456495.
- Van Dyck E, Stasiak AZ, Stasiak A, West SC (Oct 2001). "Visualization of recombination intermediates produced by RAD52-mediated single-strand annealing". EMBO Reports. 2 (10): 905–9. PMID 11571269.
- Kim PM, Allen C, Wagener BM, Shen Z, Nickoloff JA (Nov 2001). "Overexpression of human RAD51 and RAD52 reduces double-strand break-induced homologous recombination in mammalian cells". Nucleic Acids Research. 29 (21): 4352–60. PMID 11691922.
- Yáñez RJ, Porter AC (Feb 2002). "Differential effects of Rad52p overexpression on gene targeting and extrachromosomal homologous recombination in a human cell line". Nucleic Acids Research. 30 (3): 740–8. PMID 11809887.
- Jackson D, Dhar K, Wahl JK, Wold MS, Borgstahl GE (Aug 2002). "Analysis of the human replication protein A:Rad52 complex: evidence for crosstalk between RPA32, RPA70, Rad52 and DNA". Journal of Molecular Biology. 321 (1): 133–48. PMID 12139939.
- Kagawa W, Kurumizaka H, Ishitani R, Fukai S, Nureki O, Shibata T, Yokoyama S (Aug 2002). "Crystal structure of the homologous-pairing domain from the human Rad52 recombinase in the undecameric form". Molecular Cell. 10 (2): 359–71. PMID 12191481.
- Singleton MR, Wentzell LM, Liu Y, West SC, Wigley DB (Oct 2002). "Structure of the single-strand annealing domain of human RAD52 protein". Proceedings of the National Academy of Sciences of the United States of America. 99 (21): 13492–7. PMID 12370410.
- Liu J, Meng X, Shen Z (Oct 2002). "Association of human RAD52 protein with transcription factors". Biochemical and Biophysical Research Communications. 297 (5): 1191–6. PMID 12372413.
- Han J, Hankinson SE, De Vivo I, Colditz GA, Hunter DJ (Oct 2002). "No association between a stop codon polymorphism in RAD52 and breast cancer risk". Cancer Epidemiology, Biomarkers & Prevention. 11 (10 Pt 1): 1138–9. PMID 12376524.
- Kitao H, Yuan ZM (Dec 2002). "Regulation of ionizing radiation-induced Rad52 nuclear foci formation by c-Abl-mediated phosphorylation". The Journal of Biological Chemistry. 277 (50): 48944–8. PMID 12379650.