Topoisomerase II– and Condensin-Dependent Breakage of MEC1ATR-Sensitive Fragile Sites Occurs Independently of Spindle Tension, Anaphase, or Cytokinesis
| العنوان: | Topoisomerase II– and Condensin-Dependent Breakage of MEC1ATR-Sensitive Fragile Sites Occurs Independently of Spindle Tension, Anaphase, or Cytokinesis |
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| المؤلفون: | Rita S. Cha, Nadia Hashash, Anthony L. Johnson |
| المصدر: | PLoS Genetics PLoS Genetics, Vol 8, Iss 10, p e1002978 (2012) |
| بيانات النشر: | Public Library of Science, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | DNA Replication, Cancer Research, Saccharomyces cerevisiae Proteins, lcsh:QH426-470, Condensin, Mitosis, Spindle Apparatus, Protein Serine-Threonine Kinases, Microbiology, Mitotic chromosome condensation, Model Organisms, Molecular Cell Biology, Genetics, Molecular Biology, Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Anaphase, Cytokinesis, Adenosine Triphosphatases, biology, Chromosomal fragile site, Chromosome Fragile Sites, Intracellular Signaling Peptides and Proteins, Chromosome Breakage, Cell biology, DNA-Binding Proteins, lcsh:Genetics, DNA Topoisomerases, Type II, Chromosome Fragile Site, Multiprotein Complexes, Saccharomycetales, biology.protein, Chromosome breakage, Research Article, Protein Binding |
| الوصف: | Fragile sites are loci of recurrent chromosome breakage in the genome. They are found in organisms ranging from bacteria to humans and are implicated in genome instability, evolution, and cancer. In budding yeast, inactivation of Mec1, a homolog of mammalian ATR, leads to chromosome breakage at fragile sites referred to as replication slow zones (RSZs). RSZs are proposed to be homologous to mammalian common fragile sites (CFSs) whose stability is regulated by ATR. Perturbation during S phase, leading to elevated levels of stalled replication forks, is necessary but not sufficient for chromosome breakage at RSZs or CFSs. To address the nature of additional event(s) required for the break formation, we examined involvement of the currently known or implicated mechanisms of endogenous chromosome breakage, including errors in replication fork restart, premature mitotic chromosome condensation, spindle tension, anaphase, and cytokinesis. Results revealed that chromosome breakage at RSZs is independent of the RAD52 epistasis group genes and of TOP3, SGS1, SRS2, MMS4, or MUS81, indicating that homologous recombination and other recombination-related processes associated with replication fork restart are unlikely to be involved. We also found spindle force, anaphase, or cytokinesis to be dispensable. RSZ breakage, however, required genes encoding condensin subunits (YCG1, YSC4) and topoisomerase II (TOP2). We propose that chromosome break formation at RSZs following Mec1 inactivation, a model for mammalian fragile site breakage, is mediated by internal chromosomal stress generated during mitotic chromosome condensation. Author Summary Chromosome breakage can occur during normal cell division. When it occurs, the breaks do not arise randomly throughout the genome, but at preferred locations referred to as fragile sites. Chromosome breakage at fragile sites is an evolutionarily conserved phenomenon, implicated in evolution and speciation. In humans, fragile site instability is also implicated in mental retardation and cancer. Despite its biological and clinical relevance, the mechanism(s) by which breaks are introduced at mammalian fragile sites remains unresolved. Although several plausible models have been proposed, it has not been possible to ascertain their contribution, largely due to the lack of a suitable experimental system. Here, we study a yeast model system that closely recapitulates the phenomenon of chromosome breakage at mammalian fragile sites. We eliminate all but one of the currently considered models—premature compaction of the incompletely replicated genome in preparation for their segregation during cell division. We also find that the breakage required functions of three proteins involved in the genome compaction, an essential process that is evolutionarily conserved from bacteria to humans. Our findings suggest that a fundamental chromosomal process required for normal cell division can paradoxically cause genome instability and/or cell death, by triggering chromosome breakage at fragile sites. |
| اللغة: | English |
| تدمد: | 1553-7404 1553-7390 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d3bb9c52d46ff60a4c6b1ee8b5866bc9Test http://europepmc.org/articles/PMC3486896Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d3bb9c52d46ff60a4c6b1ee8b5866bc9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537404 15537390 |
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