Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis.

C Lukas; E R Kramer; J M Peters; J Bartek; J Lukas; Claus Storgaard Sørensen

Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis.

C Lukas, E R Kramer, J M Peters, J Bartek, J Lukas, Claus Storgaard Sørensen

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

95 Citationer (Scopus)

Abstract

Udgivelsesdato: 2000-Oct

Originalsprog	Engelsk
Tidsskrift	Molecular and Cellular Biology
Vol/bind	20
Udgave nummer	20
Sider (fra-til)	7613-23
Antal sider	10
ISSN	0270-7306
Status	Udgivet - 2000

Bibliografisk note

Keywords: Antibodies; Blotting, Western; CDC2-CDC28 Kinases; Carrier Proteins; Cell Cycle; Cell Cycle Proteins; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; DNA Replication; DNA-Binding Proteins; Drosophila Proteins; E2F Transcription Factors; Flow Cytometry; Fluorescent Antibody Technique; Humans; Interphase; Ligases; Macromolecular Substances; Mitosis; Protein Binding; Protein-Serine-Threonine Kinases; Saccharomyces cerevisiae Proteins; Trans-Activators; Transcription Factor DP1; Transcription Factors; Tumor Cells, Cultured; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligases

Citationsformater

@article{17ce2f40525111dd8d9f000ea68e967b,

title = "Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis.",

abstract = "Ubiquitin-proteasome-mediated destruction of rate-limiting proteins is required for timely progression through the main cell cycle transitions. The anaphase-promoting complex (APC), periodically activated by the Cdh1 subunit, represents one of the major cellular ubiquitin ligases which, in Saccharomyces cerevisiae and Drosophila spp., triggers exit from mitosis and during G(1) prevents unscheduled DNA replication. In this study we investigated the importance of periodic oscillation of the APC-Cdh1 activity for the cell cycle progression in human cells. We show that conditional interference with the APC-Cdh1 dissociation at the G(1)/S transition resulted in an inability to accumulate a surprisingly broad range of critical mitotic regulators including cyclin B1, cyclin A, Plk1, Pds1, mitosin (CENP-F), Aim1, and Cdc20. Unexpectedly, although constitutively assembled APC-Cdh1 also delayed G(1)/S transition and lowered the rate of DNA synthesis during S phase, some of the activities essential for DNA replication became markedly amplified, mainly due to a progressive increase of E2F-dependent cyclin E transcription and a rapid turnover of the p27(Kip1) cyclin-dependent kinase inhibitor. Consequently, failure to inactivate APC-Cdh1 beyond the G(1)/S transition not only inhibited productive cell division but also supported slow but uninterrupted DNA replication, precluding S-phase exit and causing massive overreplication of the genome. Our data suggest that timely oscillation of the APC-Cdh1 ubiquitin ligase activity represents an essential step in coordinating DNA replication with cell division and that failure of mechanisms regulating association of APC with the Cdh1 activating subunit can undermine genomic stability in mammalian cells.",

author = "C Lukas and Kramer, {E R} and Peters, {J M} and J Bartek and J Lukas and S{\o}rensen, {Claus Storgaard}",

note = "Keywords: Antibodies; Blotting, Western; CDC2-CDC28 Kinases; Carrier Proteins; Cell Cycle; Cell Cycle Proteins; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; DNA Replication; DNA-Binding Proteins; Drosophila Proteins; E2F Transcription Factors; Flow Cytometry; Fluorescent Antibody Technique; Humans; Interphase; Ligases; Macromolecular Substances; Mitosis; Protein Binding; Protein-Serine-Threonine Kinases; Saccharomyces cerevisiae Proteins; Trans-Activators; Transcription Factor DP1; Transcription Factors; Tumor Cells, Cultured; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligases",

year = "2000",

language = "English",

volume = "20",

pages = "7613--23",

journal = "Molecular and Cellular Biology",

issn = "0270-7306",

publisher = "American Society for Microbiology",

number = "20",

}

TY - JOUR

T1 - Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis.

AU - Lukas, C

AU - Kramer, E R

AU - Peters, J M

AU - Bartek, J

AU - Lukas, J

AU - Sørensen, Claus Storgaard

N1 - Keywords: Antibodies; Blotting, Western; CDC2-CDC28 Kinases; Carrier Proteins; Cell Cycle; Cell Cycle Proteins; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; DNA Replication; DNA-Binding Proteins; Drosophila Proteins; E2F Transcription Factors; Flow Cytometry; Fluorescent Antibody Technique; Humans; Interphase; Ligases; Macromolecular Substances; Mitosis; Protein Binding; Protein-Serine-Threonine Kinases; Saccharomyces cerevisiae Proteins; Trans-Activators; Transcription Factor DP1; Transcription Factors; Tumor Cells, Cultured; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligases

PY - 2000

Y1 - 2000

N2 - Ubiquitin-proteasome-mediated destruction of rate-limiting proteins is required for timely progression through the main cell cycle transitions. The anaphase-promoting complex (APC), periodically activated by the Cdh1 subunit, represents one of the major cellular ubiquitin ligases which, in Saccharomyces cerevisiae and Drosophila spp., triggers exit from mitosis and during G(1) prevents unscheduled DNA replication. In this study we investigated the importance of periodic oscillation of the APC-Cdh1 activity for the cell cycle progression in human cells. We show that conditional interference with the APC-Cdh1 dissociation at the G(1)/S transition resulted in an inability to accumulate a surprisingly broad range of critical mitotic regulators including cyclin B1, cyclin A, Plk1, Pds1, mitosin (CENP-F), Aim1, and Cdc20. Unexpectedly, although constitutively assembled APC-Cdh1 also delayed G(1)/S transition and lowered the rate of DNA synthesis during S phase, some of the activities essential for DNA replication became markedly amplified, mainly due to a progressive increase of E2F-dependent cyclin E transcription and a rapid turnover of the p27(Kip1) cyclin-dependent kinase inhibitor. Consequently, failure to inactivate APC-Cdh1 beyond the G(1)/S transition not only inhibited productive cell division but also supported slow but uninterrupted DNA replication, precluding S-phase exit and causing massive overreplication of the genome. Our data suggest that timely oscillation of the APC-Cdh1 ubiquitin ligase activity represents an essential step in coordinating DNA replication with cell division and that failure of mechanisms regulating association of APC with the Cdh1 activating subunit can undermine genomic stability in mammalian cells.

AB - Ubiquitin-proteasome-mediated destruction of rate-limiting proteins is required for timely progression through the main cell cycle transitions. The anaphase-promoting complex (APC), periodically activated by the Cdh1 subunit, represents one of the major cellular ubiquitin ligases which, in Saccharomyces cerevisiae and Drosophila spp., triggers exit from mitosis and during G(1) prevents unscheduled DNA replication. In this study we investigated the importance of periodic oscillation of the APC-Cdh1 activity for the cell cycle progression in human cells. We show that conditional interference with the APC-Cdh1 dissociation at the G(1)/S transition resulted in an inability to accumulate a surprisingly broad range of critical mitotic regulators including cyclin B1, cyclin A, Plk1, Pds1, mitosin (CENP-F), Aim1, and Cdc20. Unexpectedly, although constitutively assembled APC-Cdh1 also delayed G(1)/S transition and lowered the rate of DNA synthesis during S phase, some of the activities essential for DNA replication became markedly amplified, mainly due to a progressive increase of E2F-dependent cyclin E transcription and a rapid turnover of the p27(Kip1) cyclin-dependent kinase inhibitor. Consequently, failure to inactivate APC-Cdh1 beyond the G(1)/S transition not only inhibited productive cell division but also supported slow but uninterrupted DNA replication, precluding S-phase exit and causing massive overreplication of the genome. Our data suggest that timely oscillation of the APC-Cdh1 ubiquitin ligase activity represents an essential step in coordinating DNA replication with cell division and that failure of mechanisms regulating association of APC with the Cdh1 activating subunit can undermine genomic stability in mammalian cells.

M3 - Journal article

C2 - 11003657

SN - 0270-7306

VL - 20

SP - 7613

EP - 7623

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 20

ER -