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RecQ helicase genetic studies in yeast have been recently reviewed . Biochemical and genetic data indicate that RecQ helicases likely.
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- Human RecQ helicases in DNA repair, recombination, and replication. - PubMed - NCBI
- Biochemical Characteristics of RecQ Helicases
- RecQ helicases: suppressors of tumorigenesis and premature aging
A stalled form is an inherently unstable structure that will collapse if ssDNA is more The significance of this interaction has not been established, but it is likely to be physiologically relevant based on the functional interaction between E. Three separable functions for the eukaryotic RecQ helicases in replication have been proposed: Sgs1 co-localizes with Rad53 in S phase specific foci and evidence suggests that Sgs1 is required for proper association of Rad53 with chromatin.
Sgs1 appears to suppress certain types of recombination under normal circumstances and induces recombination in response to DNA damaging conditions. Despite these hyper-recombination phenotypes, sgs1 strains fail to initiate an increase in recombination in response to DNA damage, 12 a pathway that is dependent on Rad This ploidy effect is generally interpreted as the contribution of homologous recombination. These genes appear to function in independent pathways that suppress homeologous recombination.
Furthermore, in vitro assays have established RecQ family members as promiscuous helicases capable of unwinding a variety of substrates, including synthetic Holliday junctions. Given the range of known proteins that interact with Sgs1 it is possible to speculate as to the cooperation of these proteins in the resolution of aberrant DNA structures. There is a growing body of evidence linking eukaryotic RecQ helicases to the maintenance of telomeres. The short telomere is recognized by the cell as a DNA break.
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It is now widely recognized that telomere shortening is the mitotic clock that limits division capacity of most primary human cell cultures. In recent years it has been proposed that cellular senescence provides a barrier to tumorigenesis and, in humans, likely contributes to the aging of mitotically active tissues and organs. Immortalization of cells occurs by one of two mechanisms. Most cells bypass senescence by activating telomerase.
Unlike most mammalian somatic cells, yeast constitutively express telomerase and only senesce when one or more of the yeast telomerase genes are mutated. As in the human case, rare cells are able to bypass senescence by activating a RADdependent telomere-lengthening mechanism. EST2 encodes the telomerase catalytic subunit in yeast. Expression of WRN in est2 sgs1 strains can partially rescue the defect in telomere lengthening, suggesting WRN and Sgs1 may have a similar telomeric function. Telomerase-deficient yeast cultures lacking SGS1 persist for longer in senescence and those that do recover always generate telomeres with Y' amplification Type I.
The requirement of Sgs1 for generation of telomeres with TG region amplification Type II probably reflects the manner in which these types of structures are generated. The genetic link between Rad50 and Sgs1 in the formation of survivors suggests that these proteins are directly involved in the putative break-induced replication BIR mechanism of telomerase-independent telomere lengthening.
There is growing evidence that the Sgs1 telomeric function is conserved in humans. Fibroblasts cultured from WS individuals senesce more rapidly in culture than those from normal individuals, 30 , 31 although this finding has recently been challenged. There is also data indicating that WRN participates in recombination-mediated telomere lengthening. First, the rate of spontaneous immortalization of WS cell lines is very low, indicating that they may be defective in recombination- and telomerase-mediated telomere lengthening.
Given that ALT telomeres have been found in immortalized cells and tumors, it is tempting to speculate that the spectrum of tumors in RecQ diseases is shaped by a defect in the ALT pathway. Much of WS pathology occurs in slowly dividing tissues such as the dermis and vascular endothelium and not in bone marrow, epidermis and the gastrointestinal tract.
Human RecQ helicases in DNA repair, recombination, and replication. - PubMed - NCBI
This defect should be most apparent in slowly dividing tissues whose progenitor cells do not express telomerase and least apparent in actively dividing tissues. Consistent with this is the report that WS cells do not always undergo normal replicative senescence based on their inability to repress c-fos expression during senescence. Both may be different manifestations of the same defect.
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The maintenance of genome stability is crucial for the long-term viability of organisms because mutations and chromosomal rearrangements are usually cumulative. Of these, only WS, RTS and to a limited extent Cockayne's syndrome, are characterized by symptoms that resemble premature aging. The implication of these findings is that only certain types of genome instabilities give rise to premature aging phenotypes. This is also true for S.
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Mother cells divide about 20 times before dying and exhibit characteristic aging phenotypes. These include an increase in cell size, a slowing of the cell cycle, fragmentation of the nucleolus and sterility due to leaky expression from the heterochromatic mating type locus. The repeated rDNA locus is localized in the nucleolus and, in S. Stability at this locus is vital for longevity in this organism. During a yeast cell's life span, an apparently stochastic event leads to the excision of an extrachromosomal rDNA circle ERC from the rDNA locus via homologous recombination.
Recent studies of sgs1 cells indicate that the short life span of sgs1 cells is composite of two independent processes: Consistent with the two component model, deletion of FOB1 has little effect on the death rate of young sgs1 cells because this is when stochastic death exerts its greatest impact—prior to the effect of accumulating ERCs.
The short life span of sgs1 cells is a composite of aging and stochastic death. Yeast exhibit characteristic aging phenotypes such as increased cell size, a slowing of the cell cycle, fragmentation of the nucleolus, the relocalization of the Sir complex more Strains lacking SRS2 have also been shown to have a short life span that is the outcome of aging and stochastic death.
Thus, it is tempting to speculate that the increase in maximum life span in srs2 strains is also due to the suppression of aging but not the apparent DNA replication defect. ERCs and other circular DNAs are readily found in most mammalian cell types, although they do not appear to correlate with the age of the donor or passage number. However, mammals possess many more regions of repetitive DNA than yeast, and if ERCs were to occur from all of these loci, not just the rDNA, they would be difficult to detect.
This is probably true for all eukaryotes. Genome instability likely manifests itself in different ways according to the biology of the organism. Analysis of the shortened life span of sgs1 mutants reveals non-aging and aging components, both of which stem from genome instability. WS phenotypes can be understood in the same terms, as indicated in Figure 6. Model to explain sgs1 and WS phenotypes. Defects in Sgs1 or WRN lead to genome instability that is manifested as premature aging and non-aging phenotypes. Sgs1 has a defect in the first division of meiosis 6 and meiotic recombination is reduced in sgs1 strains.
This ties in with the fact that this activity is not required for interaction with Top1 or Top3 10 , or for resistance to topoisomerase inhibitors. An enormous wealth of information about the yeast RecQ has been obtained through genetic analysis. This has lead to the identification of interacting genes and the elucidation of pathways involved in DNA replication, repair and recombination. This type of analysis has also revealed the relative contribution from the various genes and pathways that are vital to the genomic stability of the organism.
In terms of the biochemical aspects of RecQ helicase function, yeast models have been employed to a lesser extent, and in this context more has been done in human cell culture. It is likely that new and relevant data could be gained from further biochemical analysis and purification of Sgs1 complexes. Although a substantial amount of data on the RecQ helicases comes from in vitro analyses, there are obvious limitations to the type of conclusions that may be drawn from in vitro work.
Under physiological conditions RecQ proteins are almost certainly never unaccompanied. As the biochemical studies have shown, interactions with other proteins likely alter substrate specificity and activity of the helicase. Moreover, it is clear that the post-transcriptional modification of RecQ proteins by phosphorylation and sumoylation can modulate the catalytic activity and localization of these proteins. A complete picture of RecQ function will only emerge from a combination of genetic, cell biological and biochemical studies.
Much of the speculation on the function of the eukaryotic RecQ proteins has relied on clues from prokaryotes. Replication, repair and recombination have been studied extensively in E.
However, there are a large number of fundamental differences between bacteria and eukaryotes that limit the usefulness of such models. Yeast has certainly proven itself to be a useful model of RecQ diseases, especially in identifying genetic interactions. A comparison of Sgs1 functions and mutant phenotypes with those of WRN illustrates how closely related they are. The fact that Sgs1 is the sole RecQ helicase in budding yeast indicates that it likely performs multiple functions that have been divided between the human RecQ helicases.
Nevertheless, the ease with which yeast can be manipulated genetically means that yeast will likely provide additional clues to the functions of WRN and the other human RecQ helicases for many years to come. Turn recording back on. National Center for Biotechnology Information , U.
Madame Curie Bioscience Database [Internet]. Show details Austin TX: Clues to Genome Instability and Aging The bacterial Escherichia coli RecQ DNA helicase is the founding member of a highly conserved family, with RecQ homologues and orthologues identified in every species examined so far. Phenotypes of RecQ Mutants Elucidation of the role of any given protein is greatly facilitated by analysis of the mutant phenotype Table 1. Table 2 Properties of fungal RecQ helicases. Structures, Substrates and Localization All RecQ helicases contain a central helicase domain, comprising amino acids with seven conserved motifs.
Figure 1 Structural comparison of yeast and human RecQ helicases. Rad51 In eukaryotes, a central step in homologous recombination is catalyzed by Rad51, , the homologue of E. Genetic Interactions The ability to perform genetic analyses in yeast allows for the rapid identification of interacting genes in a manner that is difficult to perform in mammals. Figure 4 Model for Sgs1 function at stalled replication forks and telomeres.
Telomere Maintenance There is a growing body of evidence linking eukaryotic RecQ helicases to the maintenance of telomeres.
Biochemical Characteristics of RecQ Helicases
Aging The maintenance of genome stability is crucial for the long-term viability of organisms because mutations and chromosomal rearrangements are usually cumulative. Figure 6 Model to explain sgs1 and WS phenotypes. Meiosis Sgs1 has a defect in the first division of meiosis 6 and meiotic recombination is reduced in sgs1 strains.
Summary An enormous wealth of information about the yeast RecQ has been obtained through genetic analysis. Biochemistry of homologous recombination in Escherichia coli. PMC ] [ PubMed: Courcelle J, Hanawalt PC. Participation of recombination proteins in rescue of arrested replication forks in UV-irradiated Escherichia coli need not involve recombination.
Shen J, Loeb LA. Unwinding the molecular basis of the Werner syndrome. A eukaryotic homolog of E. SGS1, a homologue of the Bloom's and Werner's syndrome genes, is required for maintenance of genome stability in Saccharomyces cerevisiae. Bloom's and Werner's syndrome genes suppress hyperrecombination in yeast sgs1 mutant: Frei C, Gasser SM.
The yeast Sgs1p helicase acts upstream of Rad53p in the DNA replication checkpoint and colocalizes with Rad53p in S-phase-specific foci. Homologous recombination is responsible for cell death in the absence of the Sgs1 and Srs2 helicases. Mankouri HW, Morgan A. The DNA helicase activity of yeast Sgs1p is essential for normal lifespan but not for resistance to topoisomerase inhibitors.
The Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase. Cohen H, Sinclair DA. Recombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase. SGS1 is required for telomere elongation in the absence of telomerase.
Sgs1 helicase activity is required for mitotic but apparently not for meiotic functions. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Studies on the ultraviolet light sensitivity of Bloom's syndrome fibroblasts. Chromosome aberrations and unscheduled DNA synthesis in X- and UV- irradiated lymphocytes from a boy with Bloom's syndrome and a man with xeroderma pigmentosum.
Evidence of clonal attenuation, clonal succession, and clonal expansion in mass cultures of aging Werner's syndrome skin fibroblasts. Mutator phenotype of Werner syndrome is characterized by extensive deletions. RecQ helicases are proposed to function during DNA replication in restoring stalled or broken replication forks, such as when the fork encounters blocking lesions or strand breaks.
Homologous recombination HR is involved in replication fork restart and repair 6. RecQ helicases resolve a variety of recombination intermediates Fig. In yeast, Sgs1 is required for stabilization of stalled replication forks induced by hydroxyurea treatment Roles for WRN and BLM in replication fork stabilization are less clear; however, they both interact with components of the replication fork.
RecQ helicases: suppressors of tumorigenesis and premature aging
RPA similarly stimulates human RecQ1 helicase Thus, RecQ helicases may function with protein partners in the processing of DNA intermediates during replication fork recovery. Alternatively, RecQ helicases may remove blocking DNA structures directly, such as G-quadruplexes, which are preferred substrates for these enzymes Fig. RecQ helicases may also resolve blocks due to excessive torsional stress induced by DNA replication or repair, via a conserved interaction with topoisomerases from E.
These blocks could contribute to replication fork stalling. RecQ helicases are also proposed to function in HR to promote proper intermediate resolution and suppress strand crossover events. HR is important for repairing chromosomal double strand breaks DSB that can result during replication when the fork encounters a single strand break SSB or gap. WS and RTS cells display an increased frequency of chromosomal rearrangements, including translocations and deletions 1 , 41 , which may result partly from DSBs.
Rad51 nucleates onto ssDNA via an interaction with Rad52 and facilitates strand invasion during recombination Suppression of recombination in some RecQ-deficient cells improves cell survival, suggesting that toxic recombination intermediates arise and persist in the absence of RecQ helicases. Similarly, the expression of a dominant-negative Rad51 mutant suppresses recombination in WS cells and increases cell survival after DNA damage However, potential roles in facilitating recombination cannot be ruled out.
Double strand breaks are repaired primarily via two pathways: WS cells show a mild to strong hypersensitivity to agents that cause DSBs: A search for protein interactions with the WRN C-terminal region identified the Ku heterodimer as the most prominent binder Therefore, some RecQ helicases may function in proper repair of SSBs, perhaps by dissociating inappropriate recombination intermediates. Whether other RecQ helicases function in pathways other than HR outside of S-phase remains to be determined. Cellular and biochemical evidence also indicate a role for RecQ helicases in maintaining telomeric ends.
WRN and BLM co-localize with TRF2 in nuclear foci of immortalized human cell lines that use a telomerase-independent pathway to prevent telomere erosion, termed ALT alternative lengthening of telomeres 55 — An ALT pathway in S.
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ALT is poorly understood, but a highly regulated form of ALT may act to repair and protect telomeric ends in normal somatic cells that lack telomerase activity. Defects in telomere structure can initiate a DNA damage response and may lead to telomeric end fusions and chromosome breakage if not properly repaired Consistent with this, WS and BS cells display some cellular features associated with defects in telomere maintenance. For example, telomere dysfunction can lead to premature senescence, which is a characteristic of WS fibroblasts These results are consistent with a possible role for RecQ helicases in repair and processing of telomeric end structures.
RecQ helicases have been proposed to function in sensing and responding to DNA damage, especially during S-phase. Evidence in yeast indicates that Sgs1 participates in the S-phase checkpoint response to DNA damage 6. Because BS cells are not hypersensitive to ionizing radiation, the role for BLM in suppressing crossover events is proposed to be important for HR associated with gaps that arise during DNA replication Thus, RecQ helicases likely play an important role in the cellular response to DNA damage, particularly during S-phase. The results summarized in this review indicate that RecQ helicases are multifunctional and likely play a role in many facets of DNA metabolism.
The complex biology of RecQ helicases presents a significant research challenge. One possible scenario is that RecQ helicases may function, in part, as transducers that act in DNA repair, replication, and recombination. Message Body Your Name thought you would like to see this page from the Biochemical Journal web site. Please log in to add an alert for this article. Open in Utopia Docs.
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