title: Essential global role of CDC14 in DNA synthesis revealed by chromosome underreplication unrecognized by checkpoints in cdc14 mutants.
abstract: The CDC14 family of multifunctional evolutionarily conserved phosphatases includes major regulators of mitosis in eukaryotes and of DNA damage response in humans. The CDC14 function is also crucial for accurate chromosome segregation, which is exemplified by its absolute requirement in yeast for the anaphase segregation of nucleolar organizers; however the nature of this essential pathway is not understood. Upon investigation of the rDNA nondisjunction phenomenon, it was found that cdc14 mutants fail to complete replication of this locus. Moreover, other late-replicating genomic regions (10% of the genome) are also underreplicated in cdc14 mutants undergoing anaphase. This selective genome-wide replication defect is due to dosage insufficiency of replication factors in the nucleus, which stems from two defects, both contingent on the reduced CDC14 function in the preceding mitosis. First, a constitutive nuclear import defect results in a drastic dosage decrease for those replication proteins that are regulated by nuclear transport. Particularly, essential RPA subunits display both lower mRNA and protein levels, as well as abnormal cytoplasmic localization. Second, the reduced transcription of MBF and SBF-controlled genes in G1 leads to the reduction in protein levels of many proteins involved in DNA replication. The failure to complete replication of late replicons is the primary reason for chromosome nondisjunction upon CDC14 dysfunction. As the genome-wide slow-down of DNA replication does not trigger checkpoints [Lengronne A, Schwob E (2002) Mol Cell 9:1067-1078], CDC14 mutations pose an overwhelming challenge to genome stability, both generating chromosome damage and undermining the checkpoint control mechanisms.
authors: National Institutes of Health, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA.
authors: Stanimir
authors: S
authors: Dulev
authors: Christelle
authors: C
authors: de Renty
authors: Rajvi
authors: R
authors: Mehta
authors: Ivan
authors: I
authors: Minkov
authors: Etienne
authors: E
authors: Schwob
authors: Alexander
authors: A
authors: Strunnikov
mesh_terms: D021581:Active Transport, Cell Nucleus; D000705:Anaphase / Q000235:genetics; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D020090:Chromosome Segregation; D015825:Chromosomes, Fungal / Q000235:genetics*; D004249:DNA Damage; D004261:DNA Replication; D004271:DNA, Fungal / Q000096:biosynthesis* / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D020043:Genes, Essential / Q000235:genetics / Q000502:physiology; D016681:Genome, Fungal / Q000235:genetics; D055106:Genome-Wide Association Study; D008954:Models, Biological; D009154:Mutation; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C074860:CDC14 protein, S cerevisiae; D018797:Cell Cycle Proteins; D004271:DNA, Fungal; D004275:DNA, Ribosomal; C082727:RFA2 protein, S cerevisiae; D051716:Replication Protein A; D029701:Saccharomyces cerevisiae Proteins; D017027:Protein Tyrosine Phosphatases