The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control

Manzano-López, Javier; Monje-Casas, Fernando

doi:10.3390/ijms21030709

Cited by 27 publications

(22 citation statements)

References 126 publications

(230 reference statements)

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“…Hutchinson-Gilford progeroid cell lines show bloated nucleoli (Buchwalter and Hetzer, 2017) and increased DNA damage that appears late in S phase (Chojnowski et al, 2020), echoing phenotypes observed in yeast strains with early replicating rDNA. Although the replication fork barrier protein Fob1p itself is not conserved in metazoans, some Cdc14p homologs are known to localize to the nucleolus (Berdougo et al, 2008;Kaiser et al, 2004;Manzano-López and Monje-Casas, 2020;Saito et al, 2004;Wu et al, 2008). Cdc14p regulation in metazoans may be more sensitive to early rDNA replication without the redundant Fob1p tether.…”

Section: Discussionmentioning

confidence: 99%

Coordination of genome replication and anaphase entry by rDNA copy number inS. cerevisiae

Kwan

Alvino

Lynch

et al. 2021

Preprint

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Ribosomal DNA (rDNA) copy number varies widely among individuals in many species, but the phenotypic consequences of such copy number fluctuations remain largely unexplored. In the yeast Saccharomyces cerevisiae, each rDNA repeat contains an origin of replication. Previous studies have demonstrated that the yeast rDNA locus can be a significant competitor for replication resources, suggesting that rDNA copy number variation may affect timely completion of genome-wide replication. We hypothesized that reduction in rDNA copy number and thus rDNA replication origins would reduce competition from the rDNA locus and thereby improve non-rDNA genome replication. To test this hypothesis, we engineered yeast strains with short rDNA arrays of 35 copies, a minimal copy number that still maintains wild type level ribosome function. Contrary to our hypothesis, the minimal rDNA strain displayed classic replication defects: decreased plasmid maintenance, delayed completion of chromosomal replication, and increased sensitivity to replication stress agonists. Although a normal rDNA array replicates late in S phase, the minimal rDNA array initiated replication in early S phase, resulting in delayed replication across the non-rDNA portions of the genome. Moreover, we discovered that absence of the rDNA fork barrier protein Fob1p increased DNA damage sensitivity in strains with early replicating rDNA. We present evidence that this increased sensitivity may be due to compromised regulation of cyclin phosphatase Cdc14p and premature entry into anaphase. Our results indicate that precocious rDNA replication, rather than total number of rDNA origins, compromises replication of the genome. Taken together, we suggest that the rDNA's large, late-replicating state is evolutionarily conserved to promote genome stability through timely genome replication and coordination of S phase completion with anaphase entry.

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Section: Discussionmentioning

confidence: 99%

Coordination of genome replication and anaphase entry by rDNA copy number inS. cerevisiae

Kwan

Alvino

Lynch

et al. 2021

Preprint

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“…The early anaphase release of Cdc14 has been linked to a variety of events necessary for the termination of mitosis (23,48) We found only one strong phenotype for the net1-6cdk allele in meiosis, a phenotype it shares with the classic FEAR mutants slk19Δ and spo12Δ -failure to disjoin the rDNA in meiosis I. From studies of mitotic cells we know that rDNA disjunction depends on two important activities of Cdc14 related to rDNA chromatin organization: condensin loading (17,20,49,50) and control of transcription within the rDNA (41,51).…”

Section: Discussionmentioning

confidence: 99%

“…The early anaphase release of Cdc14 has been linked to a variety of events necessary for the termination of mitosis (23,48) and meiosis I. However, it has been difficult to ascertain whether FEAR is directly responsible for the coincident events of chromosome segregation, spindle disassembly, spindle pole reduplication and CDK downregulation, particularly since the MEN becomes active soon after anaphase and is functionally redundant for the completion of those events.…”

Section: Discussionmentioning

confidence: 99%

Saccharomyces cerevisiaedeficient in the early anaphase release of Cdc14 can traverse anaphase I without ribosomal DNA disjunction and successfully complete meiosis

Cm¹

2021

Preprint

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Eukaryotic meiosis is a specialized cell cycle involving two successive nuclear divisions that lead to the formation of haploid gametes. The phosphatase Cdc14 plays an essential role in meiosis as revealed in studies of the yeast Saccharomyces cerevisiae . Cdc14 is stored in the nucleolus, a sub-nuclear domain containing the ribosomal DNA, and its release is regulated by two distinct pathways, one acting in early anaphase I of meiosis and a second at the exit from meiosis II. The early anaphase release is thought to be important for disjunction of the ribosomal DNA, disassembly of the anaphase I spindle, spindle pole re-duplication and the counteraction of CDK, all of which are required for progression into meiosis II. The release of Cdc14 from its nucleolar binding partner Net1 is stimulated by phosphorylation of cyclin-dependent kinase sites in Net1, but the importance of that phospho-regulation in meiosis is not well understood. We induced net1-6cdk mutant cells to enter meiosis and examined the localization of Cdc14 and various indicators of meiotic progression. The net1-6cdk mutations inhibit, but don’t fully prevent Cdc14 release, and they almost completely prevent disjunction of the ribosomal DNA during meiosis I. Failure to disjoin the ribosomal DNA is lethal in mitosis, and we expected the same to be true in meiosis. However, the cells were able to complete meiosis II, yielding the expected four meiotic products as viable spores. Therefore, all ribosomal DNA disjunction required for meiosis can occur in meiosis II. We discuss the implications of these findings for our understanding of meiotic chromosome segregation.

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“…This function of PP1 seems to be opposite to the mitotic exit promoting role of PP1 reported in animal cells. The fact that mitotic exit is achieved by the Cdc14 phosphatase in budding yeast, instead of the PP1 and PP2 phosphatases (Manzano-Lopez & Monje-Casas, 2020) is likely the reason for Glc7 gaining a different function after the anaphase onset during the narrow time window until exit from mitosis.…”

Section: Discussionmentioning

confidence: 99%

Protein Phosphatase 1 in association with Bud14 inhibits mitotic exit inSaccharomyces cerevisiae

Kocakaplan

Karabürk

Kirdök

et al. 2020

Preprint

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Saccharomyces cerevisiae, also known as the budding yeast, orients and elongates its mitotic spindle along its polarity axis in order to segregate one copy of its genomic DNA to the daughter cell. When accurate positioning of the mitotic spindle fails, a surveillance mechanism, named the Spindle Position Checkpoint (SPOC), prevents cells from exiting mitosis unless the spindle orientation is corrected. Such mitotic arrest provides cells time to align their spindle correctly before cell division is completed. Mutants with a defective SPOC loss their genomic integrity, become multiploid and aneuploid. Thus, SPOC is a crucial checkpoint for the budding yeast. Yet, a comprehensive understanding of how SPOC mechanism works is budmissing. In this study, we identified Bud14 as a novel checkpoint protein. We showed that the mitotic exit inhibitory function Bud14 requires its association with the type 1 protein phosphatase, Glc7. Cells bearing versions of Bud14 that cannot interact with Glc7 or a temperature sensitive mutant of Glc7 were SPOC deficient. Our data indicate that Glc7-Bud14 inhibits mitotic exit by promoting dephosphorylation of Bfa1 during anaphase and limiting the levels of Bfa1 at the spindle pole bodies. Our results support a model in which Glc7-Bud14 works parallel to the SPOC kinase Kin4 in regulating Bfa1, the most downstream effector of SPOC that inhibits mitotic exit.

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The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control

Cited by 27 publications

References 126 publications

Coordination of genome replication and anaphase entry by rDNA copy number inS. cerevisiae

Coordination of genome replication and anaphase entry by rDNA copy number inS. cerevisiae

Saccharomyces cerevisiaedeficient in the early anaphase release of Cdc14 can traverse anaphase I without ribosomal DNA disjunction and successfully complete meiosis

Protein Phosphatase 1 in association with Bud14 inhibits mitotic exit inSaccharomyces cerevisiae

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