RAD52 homolog (S. cerevisiae), also known as RAD52, is a protein which in humans is encoded by the RAD52 gene. [5] [6]
RAD52 homolog (S. cerevisiae), also known as RAD52, is a protein which in humans is encoded by the RAD52 gene. [5] [6]
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]
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]
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, [21] and deficiencies in DNA repair appear to underlie many forms of cancer. [22] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair. [23] [24] Such mutations and epigenetic alterations may give rise to cancer. The frequent microRNA-induced increase or deficiency of RAD52-mediated DNA repair due to microRNA binding alterations likely contributes to either the prevention or progression of breast, brain, liver or colon cancers.
RAD52 has been shown to interact with RAD51. [25] The Rad52 will ease the loading of Rad51 on ssDNA by interfering with the RPA protein.
When multiple copies of a polypeptide encoded by a gene form an aggregate, this protein structure is referred to as a multimer. When a multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. In such a case, the phenomenon is referred to as intragenic complementation. A Saccharomyces cerevisiae RAD52 mutant allele expressing a C-terminal truncated protein was found to complement other RAD52 mutant missense alleles. [26] This finding of intragenic complementation suggests that the RAD52 protein has a multimeric structure that allows cooperative interactions between the constituent monomers.
Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.
RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.
DNA repair protein RAD51 homolog 1 is a protein encoded by the gene RAD51. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA, Archaeal RadA and yeast Rad51. The protein is highly conserved in most eukaryotes, from yeast to humans.
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
DNA repair protein XRCC3 is a protein that in humans is encoded by the XRCC3 gene.
Flap endonuclease 1 is an enzyme that in humans is encoded by the FEN1 gene.
DNA repair protein RAD51 homolog 2 is a protein that in humans is encoded by the RAD51L1 gene.
RAD51 homolog C , also known as RAD51C, is a protein which in humans is encoded by the RAD51C gene.
DNA repair protein RAD51 homolog 4 is a protein that in humans is encoded by the RAD51L3 gene.
DNA repair protein XRCC2 is a protein that in humans is encoded by the XRCC2 gene.
DNA repair and recombination protein RAD54-like is a protein that in humans is encoded by the RAD54L gene.
Meiotic recombination protein DMC1/LIM15 homolog is a protein that in humans is encoded by the DMC1 gene.
DNA repair and recombination protein RAD54B is a protein that in humans is encoded by the RAD54B gene.
Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.
Homology-directed repair (HDR) is a mechanism in cells to repair double-strand DNA lesions. The most common form of HDR is homologous recombination. The HDR mechanism can only be used by the cell when there is a homologous piece of DNA present in the nucleus, mostly in G2 and S phase of the cell cycle. Other examples of homology-directed repair include single-strand annealing and breakage-induced replication. When the homologous DNA is absent, another process called non-homologous end joining (NHEJ) takes place instead.
Synthesis-dependent strand annealing (SDSA) is a major mechanism of homology-directed repair of DNA double-strand breaks (DSBs). Although many of the features of SDSA were first suggested in 1976, the double-Holliday junction model proposed in 1983 was favored by many researchers. In 1994, studies of double-strand gap repair in Drosophila were found to be incompatible with the double-Holliday junction model, leading researchers to propose a model they called synthesis-dependent strand annealing. Subsequent studies of meiotic recombination in S. cerevisiae found that non-crossover products appear earlier than double-Holliday junctions or crossover products, challenging the previous notion that both crossover and non-crossover products are produced by double-Holliday junctions and leading the authors to propose that non-crossover products are generated through SDSA.
A double-strand break repair model refers to the various models of pathways that cells undertake to repair double strand-breaks (DSB). DSB repair is an important cellular process, as the accumulation of unrepaired DSB could lead to chromosomal rearrangements, tumorigenesis or even cell death. In human cells, there are two main DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR relies on undamaged template DNA as reference to repair the DSB, resulting in the restoration of the original sequence. NHEJ modifies and ligates the damaged ends regardless of homology. In terms of DSB repair pathway choice, most mammalian cells appear to favor NHEJ rather than HR. This is because the employment of HR may lead to gene deletion or amplification in cells which contains repetitive sequences. In terms of repair models in the cell cycle, HR is only possible during the S and G2 phases, while NHEJ can occur throughout whole process. These repair pathways are all regulated by the overarching DNA damage response mechanism. Besides HR and NHEJ, there are also other repair models which exists in cells. Some are categorized under HR, such as synthesis-dependent strain annealing, break-induced replication, and single-strand annealing; while others are an entirely alternate repair model, namely, the pathway microhomology-mediated end joining (MMEJ).
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