The Antibiotic Monensin Causes Cell Cycle Disruption ofToxoplasma gondiiMediated through the DNA Repair Enzyme TgMSH-1

ABSTRACTMonensin is a polyether ionophore antibiotic that is widely used in the control of coccidia in animals. Despite its significance in veterinary medicine, little is known about its mode of action and potential mechanisms of resistance in coccidian parasites. Here we show that monensin causes accumulation of the coccidianToxoplasma gondiiat an apparent late-S-phase cell cycle checkpoint. In addition, experiments utilizing a monensin-resistantT. gondiimutant show that this effect of monensin is dependent on the function of a mitochondrial homologue of the MutS DNA damage repair enzyme (TgMSH-1). Furthermore, the same TgMSH-1-dependent cell cycle disruption is observed with the antiparasitic ionophore salinomycin and the DNA alkylating agent methyl nitrosourea. Our results suggest a novel mechanism for the mode of action of monensin and salinomycin on coccidial parasites, in which the drug activates an MSH-1-dependent cell cycle checkpoint by an unknown mechanism, ultimately leading to the death of the parasite. This model would indicate that cell cycle disruption is an important mediator of drug susceptibility and resistance to ionophoric antibiotics in coccidian parasites.

Download Full-text

A DNA-Damage-Induced Cell Cycle Checkpoint in Arabidopsis

Genetics ◽

10.1093/genetics/164.1.323 ◽

2003 ◽

Vol 164 (1) ◽

pp. 323-334

Author(s):

S B Preuss ◽

A B Britt

Keyword(s):

Cell Cycle ◽

Gamma Radiation ◽

Cell Cycle Progression ◽

Cell Cycle Checkpoint ◽

Phase Cell ◽

Cycle Arrest ◽

Cycle Checkpoint ◽

Radiation Induced ◽

High Doses ◽

Regulation Of Cell Cycle

Abstract Although it is well established that plant seeds treated with high doses of gamma radiation arrest development as seedlings, the cause of this arrest is unknown. The uvh1 mutant of Arabidopsis is defective in a homolog of the human repair endonuclease XPF, and uvh1 mutants are sensitive to both the toxic effects of UV and the cytostatic effects of gamma radiation. Here we find that gamma irradiation of uvh1 plants specifically triggers a G2-phase cell cycle arrest. Mutants, termed suppressor of gamma (sog), that suppress this radiation-induced arrest and proceed through the cell cycle unimpeded were recovered in the uvh1 background; the resulting irradiated plants are genetically unstable. The sog mutations fall into two complementation groups. They are second-site suppressors of the uvh1 mutant's sensitivity to gamma radiation but do not affect the susceptibility of the plant to UV radiation. In addition to rendering the plants resistant to the growth inhibitory effects of gamma radiation, the sog1 mutation affects the proper development of the pollen tetrad, suggesting that SOG1 might also play a role in the regulation of cell cycle progression during meiosis.

Download Full-text

Attenuation of G 2 -Phase Cell Cycle Checkpoint Control Is Associated with Increased Frequencies of Unrejoined Chromosome Breaks in Human Tumor Cells

Radiation Research ◽

10.2307/3579585 ◽

1996 ◽

Vol 146 (2) ◽

pp. 139 ◽

Cited By ~ 7

Author(s):

Jeffrey L. Schwartz ◽

Janet Cowan ◽

David J. Grdina ◽

Ralph R. Weichselbaum

Keyword(s):

Cell Cycle ◽

Tumor Cells ◽

Human Tumor ◽

Cell Cycle Checkpoint ◽

Phase Cell ◽

Checkpoint Control ◽

Human Tumor Cells ◽

Chromosome Breaks ◽

Cycle Checkpoint

Download Full-text

Cdc5L interacts with ATR and is required for the S‐phase cell‐cycle checkpoint

EMBO Reports ◽

10.1038/embor.2009.122 ◽

2009 ◽

Vol 10 (9) ◽

pp. 1029-1035 ◽

Cited By ~ 51

Author(s):

Nianxiang Zhang ◽

Ramandeep Kaur ◽

Shamima Akhter ◽

Randy J Legerski

Keyword(s):

Cell Cycle ◽

S Phase ◽

Cell Cycle Checkpoint ◽

Phase Cell ◽

Cycle Checkpoint

Download Full-text

Aberrant Expression of Nucleostemin Activates p53 and Induces Cell Cycle Arrest via Inhibition of MDM2

Molecular and Cellular Biology ◽

10.1128/mcb.01662-07 ◽

2008 ◽

Vol 28 (13) ◽

pp. 4365-4376 ◽

Cited By ~ 123

Author(s):

Mu-Shui Dai ◽

Xiao-Xin Sun ◽

Hua Lu

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Arrest ◽

Ribosomal Proteins ◽

Cell Cycle Checkpoint ◽

Aberrant Expression ◽

Cycle Arrest ◽

Reduce Cell Proliferation ◽

Cycle Checkpoint ◽

Dependent Cell

ABSTRACT The nucleolar protein nucleostemin (NS) is essential for cell proliferation and early embryogenesis. Both depletion and overexpression of NS reduce cell proliferation. However, the mechanisms underlying this regulation are still unclear. Here, we show that NS regulates p53 activity through the inhibition of MDM2. NS binds to the central acidic domain of MDM2 and inhibits MDM2-mediated p53 ubiquitylation and degradation. Consequently, ectopic overexpression of NS activates p53, induces G1 cell cycle arrest, and inhibits cell proliferation. Interestingly, the knockdown of NS by small interfering RNA also activates p53 and induces G1 arrest. These effects require the ribosomal proteins L5 and L11, since the depletion of NS enhanced their interactions with MDM2 and the knockdown of L5 or L11 abrogated the NS depletion-induced p53 activation and cell cycle arrest. These results suggest that a p53-dependent cell cycle checkpoint monitors changes of cellular NS levels via the impediment of MDM2 function.

Download Full-text