Mechanisms regulating S phase progression in mammalian cells

10.2741/3523 ◽  
2009 ◽  
Vol Volume (14) ◽  
pp. 4199 ◽  
Author(s):  
Apolinar Maya-Mendoza
Keyword(s):  
Mammalian Cells ◽  
S Phase ◽  
Phase Progression

scholarly journals WAF1 retards S-phase progression primarily by inhibition of cyclin-dependent kinases.

1997 ◽  
Vol 17 (8) ◽  
pp. 4877-4882 ◽  
Author(s):  
V V Ogryzko ◽  
P Wong ◽  
B H Howard
Keyword(s):  
Mammalian Cells ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
S Phase ◽  
In Vivo Studies ◽  
Nuclear Antigen ◽  
Phase Progression

The p21(WAF1/CIP1/sdi1) gene product (WAF1) inhibits DNA replication in vitro (J. Chen, P. Jackson, M. Kirschner, and A. Dutta, Nature 374:386-388, 1995; S. Waga, G. Hannon, D. Beach, and B. Stillman, Nature 369:574-578, 1994), but in vivo studies on the antiproliferative activity of WAF1 have not resolved G1-phase arrest from potential inhibition of S-phase progression. Here, we demonstrate that elevated WAF1 expression can retard replicative DNA synthesis in vivo. The WAF1-mediated inhibitory effect could be antagonized by cyclin A, cyclin E, or the simian virus 40 small-t antigen with no decrease in the levels of WAF1 protein in transfected cells. Proliferating-cell nuclear antigen (PCNA) overexpression was neither necessary nor sufficient to antagonize WAF1 action. Expression of the N-terminal domain of WAF1, responsible for cyclin-dependent kinase (CDK) interaction, had the same effect as full-length WAF1, while the PCNA binding C terminus exhibited modest activity. We conclude that S-phase progression in mammalian cells is dependent on continuing cyclin and CDK activity and that WAF1 affects S phase primarily through cyclin- and CDK-dependent pathways.

scholarly journals Activation of mammalian Chk1 during DNA replication arrest

2001 ◽  
Vol 154 (5) ◽  
pp. 913-924 ◽  
Author(s):  
Carmen Feijoo ◽  
Clare Hall-Jackson ◽  
Rong Wu ◽  
David Jenkins ◽  
Jane Leitch ◽  
...  
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
S Phase ◽  
Global Pattern ◽  
Origin Firing ◽  
Replication Arrest ◽  
Molecule Inhibitor ◽  
Replication Block ◽  
Phase Progression ◽  
S Phase Checkpoint

Checkpoints maintain order and fidelity in the cell cycle by blocking late-occurring events when earlier events are improperly executed. Here we describe evidence for the participation of Chk1 in an intra-S phase checkpoint in mammalian cells. We show that both Chk1 and Chk2 are phosphorylated and activated in a caffeine-sensitive signaling pathway during S phase, but only in response to replication blocks, not during normal S phase progression. Replication block–induced activation of Chk1 and Chk2 occurs normally in ataxia telangiectasia (AT) cells, which are deficient in the S phase response to ionizing radiation (IR). Resumption of synthesis after removal of replication blocks correlates with the inactivation of Chk1 but not Chk2. Using a selective small molecule inhibitor, cells lacking Chk1 function show a progressive change in the global pattern of replication origin firing in the absence of any DNA replication. Thus, Chk1 is apparently necessary for an intra-S phase checkpoint, ensuring that activation of late replication origins is blocked and arrested replication fork integrity is maintained when DNA synthesis is inhibited.

Inhibition of S-phase progression triggered by UVA-induced ROS does not require a functional DNA damage checkpoint response in mammalian cells

DNA Repair ◽  
2008 ◽  
Vol 7 (9) ◽  
pp. 1500-1516 ◽  
Author(s):  
Pierre-Marie Girard ◽  
Mariaelena Pozzebon ◽  
Fabien Delacôte ◽  
Thierry Douki ◽  
Violetta Smirnova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mammalian Cells ◽  
S Phase ◽  
Dna Damage Checkpoint ◽  
Checkpoint Response ◽  
Phase Progression ◽  
Functional Dna

scholarly journals Regulation of p27 Degradation and S-Phase Progression by Ro52 RING Finger Protein

2006 ◽  
Vol 26 (16) ◽  
pp. 5994-6004 ◽  
Author(s):  
Abdelmajid Sabile ◽  
Andrea Michael Meyer ◽  
Christiane Wirbelauer ◽  
Daniel Hess ◽  
Ulrike Kogel ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Kinase Inhibitor ◽  
Ring Finger ◽  
E3 Ligase ◽  
S Phase ◽  
Dependent Manner ◽  
Ring Finger Protein ◽  
Catalytic Core ◽  
Finger Protein ◽  
Phase Progression

ABSTRACT Ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27 provides a powerful route for enforcing normal progression through the mammalian cell cycle. According to a current model, the ubiquitination of p27 during S-phase progression is mediated by SCFSkp2 E3 ligase that captures Thr187-phosphorylated p27 by means of the F-box protein Skp2, which in turn couples the bound substrate via Skp1 to a catalytic core complex composed of Cul1 and the Rbx/Roc RING finger protein. Here we identify Skp2 as a component of an Skp1-cullin-F-box complex that is based on a Cul1-Ro52 RING finger B-box coiled-coil motif family protein catalytic core. Ro52-containing complexes display E3 ligase activity and promote the ubiquitination of Thr187-phosphorylated p27 in a RING-dependent manner in vitro. The knockdown of Ro52 expression in human cells with small interfering RNAs causes the accumulation of p27 and the failure of cells to enter S phase. Importantly, these effects are abrogated by the simultaneous removal of p27. Taken together, these data suggest a key role for Ro52 RING finger protein in the regulation of p27 degradation and S-phase progression in mammalian cells and provide evidence for the existence of a Cul1-based catalytic core that utilizes Ro52 RING protein to promote ubiquitination.

scholarly journals S-phase progression in mammalian cells: modelling the influence of nuclear organization

2010 ◽  
Vol 18 (1) ◽  
pp. 163-178 ◽  
Author(s):  
Alex Shaw ◽  
Pedro Olivares-Chauvet ◽  
Apolinar Maya-Mendoza ◽  
Dean A. Jackson
Keyword(s):  
Mammalian Cells ◽  
Nuclear Organization ◽  
S Phase ◽  
Phase Progression

scholarly journals Chromatin decondensation in S-phase involves recruitment of Cdk2 by Cdc45 and histone H1 phosphorylation

2005 ◽  
Vol 168 (6) ◽  
pp. 875-886 ◽  
Author(s):  
Mark G. Alexandrow ◽  
Joyce L. Hamlin
Keyword(s):  
Mammalian Cells ◽  
Large Scale ◽  
Histone H1 ◽  
S Phase ◽  
Wild Type ◽  
Chromatin Decondensation ◽  
Replication Foci ◽  
Phase Progression ◽  
Initiation Of Dna Replication

Cdc45 is required for initiation of DNA replication and fork progression, but its function in these processes remains unknown. We show that targeting Cdc45 to specific chromosomal sites in mammalian cells results in large-scale chromatin decondensation that strongly correlates with histone H1 phosphorylation. Cdk2 is recruited to sites of Cdc45 decondensation, and Cdk2 inhibitors reduce the level of decondensation. Targeting wild-type Cdk2, but not kinase-defective Cdk2, to chromatin is also effective at inducing decondensation involving phospho-H1. Cdc45, Cdk2, Cyclin A, and phospho-H1 associate with chromatin during S-phase, and Cdc45, Cdk2, and an active H1 kinase physically interact. Replicating DNA and phospho-H1 foci colocalize in vivo, and S-phase progression and H1 phosphorylation are directly related and Cdk2 dependent. Because Cdk2 colocalizes with replication foci and H1 regulates higher-order chromatin, we suggest a model in which Cdc45 recruits Cdk2 to replication foci, resulting in H1 phosphorylation, chromatin decondensation, and facilitation of fork progression.

scholarly journals The Meiosis-Specific Crs1 Cyclin Is Required for Efficient S-Phase Progression and Stable Nuclear Architecture

2021 ◽  
Vol 22 (11) ◽  
pp. 5483
Author(s):  
Luisa F. Bustamante-Jaramillo ◽  
Celia Ramos ◽  
Cristina Martín-Castellanos
Keyword(s):  
Cell Cycle ◽  
Translational Control ◽  
Cell Cycle Progression ◽  
Nuclear Architecture ◽  
Strand Break ◽  
Spindle Pole ◽  
S Phase ◽  
Cycle Progression ◽  
Single Wave ◽  
Phase Progression

Cyclins and CDKs (Cyclin Dependent Kinases) are key players in the biology of eukaryotic cells, representing hubs for the orchestration of physiological conditions with cell cycle progression. Furthermore, as in the case of meiosis, cyclins and CDKs have acquired novel functions unrelated to this primal role in driving the division cycle. Meiosis is a specialized developmental program that ensures proper propagation of the genetic information to the next generation by the production of gametes with accurate chromosome content, and meiosis-specific cyclins are widespread in evolution. We have explored the diversification of CDK functions studying the meiosis-specific Crs1 cyclin in fission yeast. In addition to the reported role in DSB (Double Strand Break) formation, this cyclin is required for meiotic S-phase progression, a canonical role, and to maintain the architecture of the meiotic chromosomes. Crs1 localizes at the SPB (Spindle Pole Body) and is required to stabilize the cluster of telomeres at this location (bouquet configuration), as well as for normal SPB motion. In addition, Crs1 exhibits CDK(Cdc2)-dependent kinase activity in a biphasic manner during meiosis, in contrast to a single wave of protein expression, suggesting a post-translational control of its activity. Thus, Crs1 displays multiple functions, acting both in cell cycle progression and in several key meiosis-specific events.

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