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Nucleic Acids Research Mar 2011Telomere maintenance and DNA repair are crucial processes that protect the genome against instability. RTEL1, an essential iron-sulfur cluster-containing helicase, is a... (Review)
Review
Telomere maintenance and DNA repair are crucial processes that protect the genome against instability. RTEL1, an essential iron-sulfur cluster-containing helicase, is a dominant factor that controls telomere length in mice and is required for telomere integrity. In addition, RTEL1 promotes synthesis-dependent strand annealing to direct DNA double-strand breaks into non-crossover outcomes during mitotic repair and in meiosis. Here, we review the role of RTEL1 in telomere maintenance and homologous recombination and discuss models linking RTEL1's enzymatic activity to its function in telomere maintenance and DNA repair.
Topics: Animals; DNA Helicases; Meiosis; Mice; Mitosis; Recombination, Genetic; Telomere
PubMed: 21097466
DOI: 10.1093/nar/gkq1045 -
Genomics May 2007Beckwith-Wiedemann syndrome (BWS) is a model human imprinting disorder resulting from altered activity of one or more genes in the 11p15.5 imprinted gene cluster....
Beckwith-Wiedemann syndrome (BWS) is a model human imprinting disorder resulting from altered activity of one or more genes in the 11p15.5 imprinted gene cluster. Approximately 20% of BWS cases have uniparental disomy (UPD) of chromosome 11. Such cases appear to result from mitotic recombination occurring in early embryogenesis and offer a rare opportunity to study mitotic recombination in nonneoplastic cells. We analyzed a cohort of 52 children with BWS and UPD using a panel of microsatellite markers for chromosome 11. All cases demonstrated mosaic paternal isodisomy, and IGF2 and H19 were included in the segment of UPD in all cases. However, the extent of segmental disomy was variable, with no evidence of clustering of the proximal UPD breakpoint. In most cases (92% of those informative) UPD did not involve 11q, but 4 patients demonstrated UPD for the whole of chromosome 11. In contrast to meiotic recombination, the mitotic recombination frequency did not decline near the centromere.
Topics: Beckwith-Wiedemann Syndrome; Child; Chromosomes, Human, Pair 11; DNA Methylation; Genomic Imprinting; Humans; Mitosis; Recombination, Genetic; Uniparental Disomy
PubMed: 17337339
DOI: 10.1016/j.ygeno.2007.01.005 -
BioEssays : News and Reviews in... Dec 2010Studies in the yeast Saccharomyces cerevisiae have validated the major features of the double-strand break repair (DSBR) model as an accurate representation of the... (Review)
Review
Meiotic versus mitotic recombination: two different routes for double-strand break repair: the different functions of meiotic versus mitotic DSB repair are reflected in different pathway usage and different outcomes.
Studies in the yeast Saccharomyces cerevisiae have validated the major features of the double-strand break repair (DSBR) model as an accurate representation of the pathway through which meiotic crossovers (COs) are produced. This success has led to this model being invoked to explain double-strand break (DSB) repair in other contexts. However, most non-crossover (NCO) recombinants generated during S. cerevisiae meiosis do not arise via a DSBR pathway. Furthermore, it is becoming increasingly clear that DSBR is a minor pathway for recombinational repair of DSBs that occur in mitotically-proliferating cells and that the synthesis-dependent strand annealing (SDSA) model appears to describe mitotic DSB repair more accurately. Fundamental dissimilarities between meiotic and mitotic recombination are not unexpected, since meiotic recombination serves a very different purpose (accurate chromosome segregation, which requires COs) than mitotic recombination (repair of DNA damage, which typically generates NCOs).
Topics: Chromosome Segregation; Crossing Over, Genetic; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Meiosis; Mitosis; Mutation; Recombination, Genetic; Saccharomyces cerevisiae
PubMed: 20967781
DOI: 10.1002/bies.201000087 -
Current Biology : CB Feb 2021Hybrid sterility maintains reproductive isolation between species by preventing them from exchanging genetic material. Anti-recombination can contribute to hybrid...
Hybrid sterility maintains reproductive isolation between species by preventing them from exchanging genetic material. Anti-recombination can contribute to hybrid sterility when different species' chromosome sequences are too diverged to cross over efficiently during hybrid meiosis, resulting in chromosome mis-segregation and aneuploidy. The genome sequences of the yeasts Saccharomyces cerevisiae and Saccharomyces paradoxus have diverged by about 12% and their hybrids are sexually sterile: nearly all of their gametes are aneuploid and inviable. Previous methods to increase hybrid yeast fertility have targeted the anti-recombination machinery by enhancing meiotic crossing over. However, these methods also have counteracting detrimental effects on gamete viability due to increased mutagenesis and ectopic recombination. Therefore, the role of anti-recombination has not been fully revealed, and it is often dismissed as a minor player in speciation. By repressing two genes, SGS1 and MSH2, specifically during meiosis whilst maintaining their mitotic expression, we were able to increase hybrid fertility 70-fold, to the level of non-hybrid crosses, confirming that anti-recombination is the principal cause of hybrid sterility. Breaking this species barrier allows us to generate, for the first time, viable euploid gametes containing recombinant hybrid genomes from these two highly diverged parent species.
Topics: Aneuploidy; Chromosome Segregation; Hybridization, Genetic; Meiosis; MutS Homolog 2 Protein; RecQ Helicases; Recombination, Genetic; Saccharomyces; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 33621502
DOI: 10.1016/j.cub.2020.12.038 -
Proceedings of the National Academy of... Feb 2011We carried out a population genomic survey of Saccharomyces cerevisiae diploid isolates and find that many budding yeast strains have high levels of genomic...
We carried out a population genomic survey of Saccharomyces cerevisiae diploid isolates and find that many budding yeast strains have high levels of genomic heterozygosity, much of which is likely due to outcrossing. We demonstrate that variation in heterozygosity among strains is correlated with a life-history trade-off that involves how readily yeast switch from asexual to sexual reproduction under nutrient stress. This trade-off is reflected in a negative relationship between sporulation efficiency and pseudohyphal development and correlates with variation in the expression of RME1, a transcription factor with pleiotropic effects on meiosis and filamentous growth. Selection for alternate life-history strategies in natural versus human-associated environments likely contributes to differential maintenance of genomic heterozygosity through its effect on the frequency that yeast lineages experience sexual cycles and hence the opportunity for inbreeding. In addition to elevated levels of heterozygosity, many strains exhibit large genomic regions of loss-of-heterozygosity (LOH), suggesting that mitotic recombination has a significant impact on genetic variation in this species. This study provides new insights into the roles that both outcrossing and mitotic recombination play in shaping the genome architecture of Saccharomyces cerevisiae. This study also provides a unique case where stark differences in the genomic distribution of genetic variation among individuals of the same species can be largely explained by a life-history trade-off.
Topics: Evolution, Molecular; Genome, Fungal; Loss of Heterozygosity; Mitosis; Recombination, Genetic; Saccharomyces cerevisiae; Spores, Fungal
PubMed: 21245305
DOI: 10.1073/pnas.1012544108 -
Genetics Oct 2002We have made a comparative analysis of double-strand-break (DSB)-induced recombination and spontaneous recombination under low- and high-transcription conditions in...
We have made a comparative analysis of double-strand-break (DSB)-induced recombination and spontaneous recombination under low- and high-transcription conditions in yeast. We constructed two different recombination substrates, one for the analysis of intermolecular gene conversions and the other for intramolecular gene conversions and inversions. Such substrates were based on the same leu2-HOr allele fused to the tet promoter and containing a 21-bp HO site. Gene conversions and inversions were differently affected by rad1, rad51, rad52, and rad59 single and double mutations, consistent with the actual view that such events occur by different recombination mechanisms. However, the effect of each mutation on each type of recombination event was the same, whether associated with transcription or induced by the HO-mediated DSB. Both the highly transcribed DNA and the HO-cut sequence acted as recipients of the gene conversion events. These results are consistent with the hypothesis that transcription promotes initiation of recombination along the DNA sequence being transcribed. The similarity between transcription-associated and DSB-induced recombination suggests that transcription promotes DNA breaks.
Topics: Chromosome Inversion; DNA Damage; DNA Repair Enzymes; DNA-Binding Proteins; Endonucleases; Gene Conversion; Rad51 Recombinase; Rad52 DNA Repair and Recombination Protein; Recombination, Genetic; Repetitive Sequences, Nucleic Acid; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription, Genetic
PubMed: 12399375
DOI: 10.1093/genetics/162.2.603 -
Nucleic Acids Research 2006Homologous recombination (HR) is a ubiquitous cellular pathway that mediates transfer of genetic information between homologous or near homologous (homeologous) DNA... (Review)
Review
Homologous recombination (HR) is a ubiquitous cellular pathway that mediates transfer of genetic information between homologous or near homologous (homeologous) DNA sequences. During meiosis it ensures proper chromosome segregation in the first division. Moreover, HR is critical for the tolerance and repair of DNA damage, as well as in the recovery of stalled and broken replication forks. Together these functions preserve genomic stability and assure high fidelity transmission of the genetic material in the mitotic and meiotic cell divisions. This review will focus on the Rad54 protein, a member of the Snf2-family of SF2 helicases, which translocates on dsDNA but does not display strand displacement activity typical for a helicase. A wealth of genetic, cytological, biochemical and structural data suggests that Rad54 is a core factor of HR, possibly acting at multiple stages during HR in concert with the central homologous pairing protein Rad51.
Topics: Adenosine Triphosphatases; DNA Helicases; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Models, Biological; Rad52 DNA Repair and Recombination Protein; Recombination, Genetic; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription Factors
PubMed: 16935872
DOI: 10.1093/nar/gkl481 -
BMC Medical Genetics Jun 2009Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH). Although meiotic recombination maps are...
BACKGROUND
Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH). Although meiotic recombination maps are plentiful, little is known about mitotic recombination. The APC gene (chr5q21) is mutated in most colorectal tumours and its usual mode of LOH is mitotic recombination.
METHODS
We mapped mitotic recombination boundaries ("breakpoints") between the centromere (~50 Mb) and APC (~112 Mb) in early colorectal tumours.
RESULTS
Breakpoints were non-random, with the highest frequency between 65 Mb and 75 Mb, close to a low copy number repeat region (68-71 Mb). There were, surprisingly, few breakpoints close to APC, contrary to expectations were there constraints on tumorigenesis caused by uncovering recessive lethal alleles or if mitotic recombination were mechanistically favoured by a longer residual chromosome arm. The locations of mitotic and meiotic recombination breakpoints were correlated, suggesting that the two types of recombination are influenced by similar processes, whether mutational or selective in origin. Breakpoints were also associated with higher local G+C content. The recombination and gain/deletion breakpoint maps on 5q were not, however, associated, perhaps owing to selective constraints on APC dosage in early colorectal tumours. Since polymorphisms within the region of frequent mitotic recombination on 5q might influence the frequency of LOH, we tested the 68-71 Mb low copy number repeat and nearby tagSNPs, but no associations with colorectal cancer risk were found.
CONCLUSION
LOH on 5q is non-random, but local factors do not greatly influence the rate of LOH at APC or explain inter differential susceptibility to colorectal tumours.
Topics: Cell Line, Tumor; Chromosome Mapping; Chromosomes, Human, Pair 5; Colorectal Neoplasms; Genes, APC; Genetic Predisposition to Disease; Humans; Loss of Heterozygosity; Microsatellite Repeats; Mitosis; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Recombination, Genetic; Sequence Analysis, DNA
PubMed: 19515250
DOI: 10.1186/1471-2350-10-54 -
Cancer Science Dec 2014Double-strand breaks (DSBs) are one of the severest types of DNA damage. Unrepaired DSBs easily induce cell death and chromosome aberrations. To maintain genomic... (Review)
Review
Double-strand breaks (DSBs) are one of the severest types of DNA damage. Unrepaired DSBs easily induce cell death and chromosome aberrations. To maintain genomic stability, cells have checkpoint and DSB repair systems to respond to DNA damage throughout most of the cell cycle. The failure of this process often results in apoptosis or genomic instability, such as aneuploidy, deletion, or translocation. Therefore, DSB repair is essential for maintenance of genomic stability. During mitosis, however, cells seem to suppress the DNA damage response and proceed to the next G1 phase, even if there are unrepaired DSBs. The biological significance of this suppression is not known. In this review, we summarize recent studies of mitotic DSB repair and discuss the mechanisms of suppression of DSB repair during mitosis. DSB repair, which maintains genomic integrity in other phases of the cell cycle, is rather toxic to cells during mitosis, often resulting in chromosome missegregation and aberration. Cells have multiple safeguards to prevent genomic instability during mitosis: inhibition of 53BP1 or BRCA1 localization to DSB sites, which is important to promote non-homologous end joining or homologous recombination, respectively, and also modulation of the non-homologous end joining core complex to inhibit DSB repair. We discuss how DSBs during mitosis are toxic and the multiple safeguard systems that suppress genomic instability.
Topics: Animals; Cell Cycle Proteins; Chromosome Aberrations; DNA Breaks, Double-Stranded; DNA Repair; Genomic Instability; Humans; Mitosis; Recombination, Genetic
PubMed: 25287622
DOI: 10.1111/cas.12551 -
The EMBO Journal Nov 1990Molecular evidence for intrachromosomal recombination between closely linked DNA repeats within the plant genome is presented. The non-overlapping complementary deletion...
Molecular evidence for intrachromosomal recombination between closely linked DNA repeats within the plant genome is presented. The non-overlapping complementary deletion derivatives of the selectable neomycin phosphotransferase gene (nptII), when intact conferring kanamycin resistance, were inserted into the genome of Nicotiana tabacum. The functional marker gene was restored with frequencies between 10(-4) and 10(-6) per proliferating cell clone. Prolonged tissue culture prior to kanamycin selection did not increase the number of recombinant kanamycin-resistant (KanR) cell clones. DNA analysis of KanR clones derived from cells carrying multiple tandem recombination units suggested that these units have a tendency to undergo concerted recombination. Recovery and analysis of kanamycin-sensitive seedlings with patches of KanR cells provided direct evidence for mitotic recombination in plant tissue.
Topics: Base Sequence; Blotting, Southern; Cell Line; Chromosomes; Cloning, Molecular; In Vitro Techniques; Kanamycin Kinase; Meiosis; Mitosis; Molecular Sequence Data; Phosphotransferases; Plants, Toxic; Recombination, Genetic; Restriction Mapping; Nicotiana
PubMed: 2170114
DOI: 10.1002/j.1460-2075.1990.tb07551.x