The CDC-14 phosphatase controls developmental cell-cycle arrest in C. elegans

Saito, R. Mako; Perreault, Audrey; Peach, Bethan; Satterlee, John S.; Heuvel, Sander van den

doi:10.1038/ncb1154

Cited by 89 publications

(114 citation statements)

References 29 publications

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“…The genetic interactions of C. elegans THAP proteins with LIN-35͞Rb (8,9,13,20) and our observation that the zebrafish orthologue of cell-cycle transcription factor E2F6 contains a THAP domain (Fig. 1) suggest important roles for THAP proteins in cell proliferation and͞or cell-cycle progression.…”

Section: Discussionmentioning

confidence: 98%

“…The multi-THAP C. elegans protein HIM-17 has been shown to be associated with chromatin and required for proper accumulation of histone H3 methylation at lysine-9 on meiotic prophase chromosomes (8), suggesting that HIM-17 recruits chromatin-modifying and͞or -remodeling complexes essential for chromatin modification during meiosis. The link between THAP proteins and chromatin modification͞remodeling is further reinforced by the observation that five distinct C. elegans proteins containing consensus and͞or divergent THAP domains (LIN-36, LIN-15B, HIM-17, CDC-14B, and LIN-15A) have been shown to interact genetically with LIN-35͞Rb (8,9,13,20), a known component of chromatin-remodeling complexes in mammalian cells (30). Interestingly, human THAP7 has recently been found to associate with chromatin and to function as a histone-tail-binding protein that represses transcription through recruitment of corepressor NcoR and histone deacetylase HDAC3 (6).…”

Section: Discussionmentioning

confidence: 99%

“…1B) gave additional interesting clues to the biological roles of THAP proteins in vivo. In addition to the recently described chromatinassociated protein HIM-17 and cell-cycle regulators LIN-15B and LIN-36 (8, 13), we identified five other proteins exhibiting consensus THAP motifs in C. elegans, including CDC-14B, an isoform of cell-cycle regulator tyrosine phosphatase CDC-14 (20), which contains both consensus and divergent THAP motifs at its carboxyl terminus. The C. elegans THAP family also included three previously uncharacterized proteins (Table 2 and Fig.…”

Section: A Comprehensive List Of Thap Proteins In Model Organismsmentioning

confidence: 99%

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The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity

Clouaire

Roussigné

Ecochard

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

135

193

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We have recently described an evolutionarily conserved protein motif, designated the THAP domain, which defines a previously uncharacterized family of cellular factors (THAP proteins). The THAP domain exhibits similarities to the site-specific DNA-binding domain of Drosophila P element transposase, including a putative metal-coordinating C2CH signature (CX 2-4CX35-53CX2H). In this article, we report a comprehensive list of Ϸ100 distinct THAP proteins in model animal organisms, including human nuclear proapoptotic factors THAP1 and DAP4͞THAP0, transcriptional repressor THAP7, zebrafish orthologue of cell cycle regulator E2F6, and Caenorhabditis elegans chromatin-associated protein HIM-17 and cell-cycle regulators LIN-36 and LIN-15B. In addition, we demonstrate the biochemical function of the THAP domain as a zinc-dependent sequence-specific DNA-binding domain belonging to the zincfinger superfamily. In vitro binding-site selection allowed us to identify an 11-nucleotide consensus DNA-binding sequence specifically recognized by the THAP domain of human THAP1. Mutations of single nucleotide positions in this sequence abrogated THAP-domain binding. Experiments with the zinc chelator 1,10-ophenanthroline revealed that the THAP domain is a zinc-dependent DNA-binding domain. Site-directed mutagenesis of single cysteine or histidine residues supported a role for the C2CH motif in zinc coordination and DNA-binding activity. The four other conserved residues (P, W, F, and P), which define the THAP consensus sequence, were also found to be required for DNA binding. Together with previous genetic data obtained in C. elegans, our results suggest that cellular THAP proteins may function as zincdependent sequence-specific DNA-binding factors with roles in proliferation, apoptosis, cell cycle, chromosome segregation, chromatin modification, and transcriptional regulation.protein motif ͉ zinc finger ͉ Caenorhabditis elegans ͉ cell cycle W e have recently described an evolutionarily conserved Ϸ90-residue protein motif, designated the THAP domain, which defines a previously uncharacterized family of cellular factors, the THAP proteins (1, 2). This motif is characterized by a putative metal-coordinating C2CH module (CX 2-4 CX 35-53 CX 2 H) and four additional invariant residues, P26, W36, F58, and P78, in human THAP1 (Fig. 1). The THAP domain was found to be restricted to animals and is present in both vertebrates (from zebrafish to humans) and invertebrates (e.g., fly and worm) (1). Interestingly, the THAP-motif signature was identified (1) in the site-specific DNA-binding domain of Drosophila melanogaster P element transposase (3). This finding suggested that the THAP domain may constitute an example of a DNA-binding domain shared between cellular proteins and transposases from mobile genomic parasites and that the THAP proteins may correspond to a previously uncharacterized family of cellular DNA-binding proteins (1).In humans, the THAP family comprises 12 distinct members, including nuclear proapoptotic factor THAP1 (2), death-...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: A Comprehensive List Of Thap Proteins In Model Organismsmentioning

confidence: 99%

See 1 more Smart Citation

The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity

Clouaire

Roussigné

Ecochard

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

135

193

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“…17 However, a subsequent study reached the opposite conclusion, finding that null cdc-14 worms are viable and lack discernable mitotic and/or cytokinetic defects. 18 Mammals possess two distinct Cdc14 isoforms, termed Cdc14A and Cdc14B, which localize to the centrosome and nucleolus respectively in interphase, but are then dispersed at onset of mitosis. 19,20 While Cdc14B has been suggested to regulate interphase nuclear architecture, 21 mitotic spindle assembly, 22 and M phase exit, 23 direct evidence in support of these proposed functions has been lacking, at least in part because of incomplete silencing of Cdc14B expression via RNA interference.…”

Section: Introductionmentioning

confidence: 99%

The nucleolar phosphataseCdc14Bis dispensable for chromosome segregation and mitotic exit in human cells

Berdougo¹,

Nachury²,

Jackson³

et al. 2008

Cell Cycle

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In yeast, the protein phosphatase Cdc14 promotes chromosome segregation, mitotic exit, and cytokinesis by reversing M-phase phosphorylations catalyzed by Cdk1. A key feature of Cdc14 regulation is its sequestration within the nucleolus, which restricts its access to potential substrates for much of the cell cycle. Mammals also possess a nucleolar Cdc14 homolog, termed Cdc14B, but its roles during mitosis and cell division remain speculative. Here we analyze Cdc14B's subcellular dynamics during mitosis and rigorously test its functional contributions to cell division through homozygous disruption of the Cdc14B locus in human somatic cells. While Cdc14B is initially released from nucleoli at the start of mitosis, the phosphatase quickly redistributes onto segregating sister chromatids during anaphase. This relocalization is mainly driven by Cdk1 inactivation, as pharmacologic inhibition of Cdk1 in prometaphase cells redirects Cdc14B onto chromosomes. However, in sharp contrast to yeast cdc14 mutants, human Cdc14B Δ/Δ cells were viable and lacked defects in spindle assembly, anaphase progression, mitotic exit, and cytokinesis, and continued to segregate ribosomal DNA repeats with near-normal proficiency. Our findings reveal substantial divergence in mitotic regulation between yeast and mammalian cells, as the latter possess efficient mechanisms for completing late M-phase events in the absence of a nucleolar Cdc14-related phosphatase.

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“…7,8 Homologues of Cdc14 with roles in cell division processes and cytokinesis have also been identified in Caenorhabditis elegans and Xenopus. [9][10][11] In human cells, two Cdc14 isoforms -Cdc14A and Cdc14B-have been identified. 12 The function of these phosphatases remains poorly understood, although it is known that Cdc14A plays an important role in the centrosome cycle and mitotic regulation.…”

Section: Introductionmentioning

confidence: 99%