Disease relevance of SGS1

• All of these phenotypic consequences of loss of Top3p function are at least partially suppressed by deletion of SGS1, the yeast homologue of the human Bloom's and Werner's syndrome genes [1].
• Late-generation sgs1 and srs2 cells senesce due to apparent premature aging, most likely involving the accumulation of extrachromosomal rDNA circles [2].
• Mutation of SGS1 is shown to cause premature aging in yeast mother cells on the basis of a shortened life-span and the aging-induced phenotypes of sterility and redistribution of the Sir3 silencing protein from telomeres to the nucleolus [3].
• In contrast, the SGS1 K(706)-->A allele was sufficient to rescue the hypersensitivity of the sgs1Delta strain to topoisomerase inhibitors, but not other genotoxic agents [4].
• Sgs1: a eukaryotic homolog of E. coli RecQ that interacts with topoisomerase II in vivo and is required for faithful chromosome segregation [5].

High impact information on SGS1

• The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination-derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase [6].
• We used SGS1 and SRS2, two 3'-->5' DNA helicase genes, as 'queries' to identify their redundant and unique biological functions [7].
• Relatively little is known about the function of Sgs1p because single mutations in SGS1 do not generally cause strong phenotypes [8].
• Epistasis analysis showed that Sgs1p is redundant with DNA mismatch repair (MMR) for suppressing GCRs and for suppressing recombination between divergent DNA sequences [8].
• Mutations in SGS1 increased the rate of accumulating gross chromosomal rearrangements (GCRs), including translocations and deletions containing extended regions of imperfect homology at their breakpoints. sgs1 mutations also increased the rate of recombination between DNA sequences that had 91% sequence homology [8].

Chemical compound and disease context of SGS1

• The Top3-Sgs1(Delta1-106) and Top3-Sgs1(V29E) fusion proteins behave like wild-type Sgs1 in complementing several aspects of the sgs1 phenotype, including the hypersensitivity of sgs1 cells to methyl methanesulfonate and hydroxyurea [9].

Biological context of SGS1

• And like top3 strains, most rmi1 phenotypes are suppressed by mutations in SGS1 [10].
• Genome stability requires a set of RecQ-Top3 DNA helicase-topoisomerase complexes whose sole budding yeast homolog is encoded by SGS1-TOP3 [10].
• The Saccharomyces cerevisiae mismatch repair (MMR) protein MSH6 and the SGS1 helicase were recently shown to play similarly important roles in preventing recombination between divergent DNA sequences in a single-strand annealing (SSA) assay [11].
• We previously reported that budding yeast cells deficient in SGS1 showed an increase in the frequency of recombination between unequal sister chromatids recombination (USCR) [12].
• Similarly, mutation in SGS1, the RECQ homologue in budding yeast, results in genomic instability and accelerated ageing [13].

Anatomical context of SGS1

• Bloom's and Werner's syndrome cell lines both exhibit chromosomal instability, sgs1 delta strains show mitotic hyperrecombination, as do Bloom's cells [14].

Associations of SGS1 with chemical compounds

• Disruption of SGS1 results in high sensitivity to methyl methanesulfonate (MMS), poor sporulation, and a hyper-recombination phenotype including recombination between heteroalleles [15].
• Furthermore, we found that multiple copies of SGS1, a gene encoding a helicase that can unwind guanine quadruplexes, inhibited suppression of the cdc13-1 phenotype by STM1 [16].
• In this study, we found that several amino acids residues in the N-terminal region of Sgs1 between residues 4 and 33 were responsible for binding to Top3 and essential for complementing the sensitivity to MMS of sgsl cells [17].
• In this study, we examined whether Sgs1 prevents formation of DNA double strand breaks (DSBs) or is involved in DSB repair following exposure to methyl methanesulfonate (MMS) [18].
• Disruption of the SGS1 gene is associated with high sensitivity to methyl methanesulfonate (MMS) and hydroxyurea (HU), and with hyper-recombination phenotypes, including interchromosomal recombination between heteroalleles [19].

Physical interactions of SGS1

• We show that Rmi1 forms a heteromeric complex with Sgs1-Top3 in yeast and that these proteins interact directly in a recombinant system [10].
• In this report, we show that yeast Mlh3 co-immunoprecipitates with Sgs1 helicase in sporulating cells at late stage of meiotic prophase I [20].
• We have recently shown that Sgs1p interacts with the DNA repair Rad16p protein and is epistatic to Rad16p for UVC, 4-NQO and H2O2 lesions [21].
• These results indicate that the 3' to 5' polarity of unwinding by the recombinant Sgs1 protein is a direct consequence of the binding of the helicase to the single-stranded/double-stranded DNA junction and its recognition of the polarity of the single-stranded DNA at the junction [22].

Regulatory relationships of SGS1

• Involvement of SGS1 in DNA damage-induced heteroallelic recombination that requires RAD52 in Saccharomyces cerevisiae [15].
• Interestingly, an extra copy of YKU70 partially suppressed the increase in targeted integration seen in the sgs1 single mutant [23].
• Sgs1 regulates gene conversion tract lengths and crossovers independently of its helicase activity [24].

Other interactions of SGS1

• We present a model wherein Rad51 helps recruit Sgs1-Top3 to sites of replicative damage [25].
• In this study, we found that SGS1 forms part of the RAD52 epistasis group when cells are exposed to MMS [15].
• Replication fork bypass processes appear to be highly conserved within eukaryotes, with homologs for SGS1 and MGS1 found in both Schizosaccharomyces pombe and mammalian cells [26].
• Roles of SGS1, MUS81, and RAD51 in the repair of lagging-strand replication defects in Saccharomyces cerevisiae [27].
• Here, we report the isolation and characterization of temperature-sensitive (ts) SGS1 alleles in cells lacking SLX4 [28].

Analytical, diagnostic and therapeutic context of SGS1

• Further dissection of the sgs1 and srs2 survival curves reveals two distinct phenomena [2].
• Two-hybrid assays suggested that the region of Top3 responsible for the binding to Sgs1 was bipartite, with portion in the N- and C-terminal domains [17].
• An analysis by pulsed-field gel electrophoresis and epistasis analyses indicated that Sgs1 is required for DSB repair that involves Rad52 [18].
• Affinity chromatography experiments with various fragments of Sgs1, a 1447-amino acid polypeptide, suggested that its N-terminal one-fifth was sufficient for interaction with DNA topoisomerase III [29].
• A fragment of the Sftps1 gene in this strain was also cloned by degenerate PCR using the CoDeHOP strategy and multiply-aligned Tps1 sequences [30].

References