Subject(s)
Global Health , Universal Health Insurance , France , Human Rights , Humans , International Cooperation , PhilosophySubject(s)
Women's Health , Women's Rights , Advisory Committees , Female , Global Health , Humans , International Cooperation , Power, Psychological , Reproductive RightsSubject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Squamous Cell/radiotherapy , Medical Oncology , Mouth Neoplasms , Tongue Neoplasms , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Disease-Free Survival , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Fluorouracil/therapeutic use , Humans , International Cooperation , Mouth Neoplasms/drug therapy , Mouth Neoplasms/radiotherapy , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/therapeutic use , Oxaliplatin , Palliative Care , Singapore , Tongue Neoplasms/drug therapy , Tongue Neoplasms/radiotherapyABSTRACT
Mitotic chromosome segregation requires the removal of physical connections between sister chromatids. In addition to cohesin and topological entrapments, sister chromatid separation can be prevented by the presence of chromosome junctions or ongoing DNA replication. We will collectively refer to them as DNA-mediated linkages. Although this type of structures has been documented in different DNA replication and repair mutants, there is no known essential mechanism ensuring their timely removal before mitosis. Here, we show that the dissolution of these connections is an active process that requires the Smc5/6 complex, together with Mms21, its associated SUMO-ligase. Failure to remove DNA-mediated linkages causes gross chromosome missegregation in anaphase. Moreover, we show that Smc5/6 is capable to dissolve them in metaphase-arrested cells, thus restoring chromosome resolution and segregation. We propose that Smc5/6 has an essential role in the removal of DNA-mediated linkages to prevent chromosome missegregation and aneuploidy.
Subject(s)
Cell Cycle Proteins/physiology , Chromatids/metabolism , Chromosome Segregation , Saccharomyces cerevisiae Proteins/physiology , Cell Cycle Proteins/genetics , Chromatids/chemistry , DNA Replication/drug effects , DNA, Fungal/chemistry , DNA, Fungal/metabolism , Genome, Fungal/drug effects , Methyl Methanesulfonate/toxicity , Mutation , Saccharomyces cerevisiae Proteins/geneticsSubject(s)
Adolescent, Hospitalized , Charities , Neoplasms/therapy , Social Support , Adolescent , Adolescent Health Services , Humans , United Kingdom , Young AdultABSTRACT
Translocations in chromosomes alter genetic information. Although the frequent translocations observed in many tumors suggest the altered genetic information by translocation could promote tumorigenesis, the mechanisms for how translocations are suppressed and produced are poorly understood. The smc6-9 mutation increased the translocation class gross chromosomal rearrangement (GCR). Translocations produced in the smc6-9 strain are unique because they are non-reciprocal and dependent on break-induced replication (BIR) and independent of non-homologous end joining. The high incidence of translocations near repetitive sequences such as delta sequences, ARS, tRNA genes, and telomeres in the smc6-9 strain indicates that Smc5-Smc6 suppresses translocations by reducing DNA damage at repetitive sequences. Synergistic enhancements of translocations in strains defective in DNA damage checkpoints by the smc6-9 mutation without affecting de novo telomere addition class GCR suggest that Smc5-Smc6 defines a new pathway to suppress GCR formation.
Subject(s)
Cell Cycle Proteins/physiology , Chromosome Aberrations , Saccharomyces cerevisiae Proteins/physiology , DNA Damage , DNA Replication , Repetitive Sequences, Nucleic Acid , Telomere/physiology , Translocation, GeneticABSTRACT
DNA double-strand breaks (DSB) can arise during DNA replication, or after exposure to DNA-damaging agents, and their correct repair is fundamental for cell survival and genomic stability. Here, we show that the Smc5-Smc6 complex is recruited to DSBs de novo to support their repair by homologous recombination between sister chromatids. In addition, we demonstrate that Smc5-Smc6 is necessary to suppress gross chromosomal rearrangements. Our findings show that the Smc5-Smc6 complex is essential for genome stability as it promotes repair of DSBs by error-free sister-chromatid recombination (SCR), thereby suppressing inappropriate non-sister recombination events.
Subject(s)
Cell Cycle Proteins/physiology , DNA Damage , Saccharomyces cerevisiae Proteins/physiology , Saccharomyces cerevisiae/physiology , Sister Chromatid Exchange , DNA/metabolism , Deoxyribonucleases, Type II Site-Specific/metabolism , Genomic Instability , Saccharomyces cerevisiae/geneticsABSTRACT
Cell cultures represent versatile and useful experimental models of transmissible spongiform encephalopathies. These models include chronically prion infected cell lines, as well as cultures expressing variable amounts of wild-type, mutated or chimeric prion proteins. These cultures have been widely used to investigate the biology of both the normal and the pathological isoform of the prion protein. They have also contributed to the comprehension of the pathogenic processes occurring in transmissible spongiform encephalopathies and in the development of new therapeutic approaches of these diseases.