ATR Homolog Mec1 Is Differentially Regulated at Different Times of DNA Damage Dependent Cell Cycle Arrest

Abstract DNA topoisomerases, enzymes that alter the superhelicity of DNA, have been implicated in such critical cellular functions as transcription, DNA replication, and recombination. In the yeast Saccharomyces cerevisiae, a null mutation in the gene encoding topoisomerase I (TOP1) causes elevated levels of mitotic recombination in the ribosomal DNA (rDNA), but has little effect on growth. We have isolated a missense mutation in TOP1 that causes mitotic hyper-recombination not only in the rDNA, but also at other loci, in addition to causing a number of other unexpected phenotypes. This topoisomerase I mutation (top1-103) causes slow growth, constitutive expression of DNA damage-inducible genes, and inviability in the absence of the double-strand break repair system. Overexpression of top1-103 causes RAD9-dependent cell cycle arrest in G2. We show that the Top1-103 enzyme nicks DNA in vitro, suggesting that it damages DNA directly. We propose that Top1-103 mimics the action of wild-type topoisomerase I in the presence of the anti-tumor drug, camptothecin.

Download Full-text

Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis

Journal of Biological Chemistry ◽

10.1074/jbc.m115.676437 ◽

2015 ◽

Vol 290 (46) ◽

pp. 27986-28000 ◽

Cited By ~ 17

Author(s):

Meng Lu ◽

Chiara Boschetti ◽

Alan Tunnacliffe

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cycle Arrest ◽

Dependent Cell

Download Full-text

Methylation of histone H4 lysine 20 by PR-Set7 ensures the integrity of late replicating sequence domains in Drosophila

10.1101/028100 ◽

2015 ◽

Author(s):

Yulong Li () ◽

Robin L. Armstrong ◽

Robert J. Duronio ◽

David M. MacAlpine

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Replication ◽

Cell Cycle Arrest ◽

Mammalian Cells ◽

Genome Stability ◽

Histone H4 ◽

Cycle Arrest ◽

Genomic Scale ◽

Dependent Cell

ABSTRACTThe methylation state of lysine 20 on histone H4 (H4K20) has been linked to chromatin compaction, transcription, DNA repair and DNA replication. Monomethylation of H4K20 (H4K20me1) is mediated by the cell cycle-regulated histone methyltransferase PR-Set7. PR-Set7 depletion in mammalian cells results in defective S phase progression and the accumulation of DNA damage, which has been partially attributed to defects in origin selection and activation. However, these studies were limited to only a handful of mammalian origins, and it remains unclear how PR-Set7 and H4K20 methylation impact the replication program on a genomic scale. We employed genetic, cytological, and genomic approaches to better understand the role of PR-Set7 and H4K20 methylation in regulating DNA replication and genome stability in Drosophila cells. We find that deregulation of H4K20 methylation had no impact on origin activation throughout the genome. Instead, depletion of PR-Set7 and loss of H4K20me1 results in the accumulation of DNA damage and an ATR-dependent cell cycle arrest. Coincident with the ATR-dependent cell cycle arrest, we find increased DNA damage that is specifically limited to late replicating regions of the Drosophila genome, suggesting that PR-Set7-mediated monomethylation of H4K20 is critical for maintaining the genomic integrity of late replicating domains.

Download Full-text

Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

Molecules ◽

10.3390/molecules26051453 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1453

Author(s):

Haoran Wang ◽

Jianhua Wei ◽

Hong Jiang ◽

Ye Zhang ◽

Caina Jiang ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Antitumor Agents ◽

Mechanistic Study ◽

Ros Generation ◽

Polypyridyl Complexes ◽

Expression Levels ◽

Cycle Arrest ◽

Study Results

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds 6a and 6c exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, 6a effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of 6a and 6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that 6a and 6c arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, 6a and 6c caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that 6a and 6c exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.

Download Full-text

ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)84970-9 ◽

2002 ◽

Vol 277 (23) ◽

pp. 21110 ◽

Cited By ~ 1

Author(s):

Damu Tang ◽

Dongcheng Wu ◽

Atsushi Hirao ◽

Jill M. Lahti ◽

Lieqi Liu ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Erk Activation ◽

Cycle Arrest

Download Full-text

P28-10 Cisplatin induces DNA damage associated with cell cycle arrest and apoptosis in PC9 cells

Annals of Oncology ◽

10.1016/j.annonc.2021.05.736 ◽

2021 ◽

Vol 32 ◽

pp. S346

Author(s):

Md Mohiuddin ◽

Hideharu Kimura ◽

Takashi Sone ◽

Hiroki Matsuoka ◽

Keigo Saeki ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cycle Arrest

Download Full-text

Aqueous Extracts of the Edible Gracilaria tenuistipitata are Protective Against H2O2-Induced DNA Damage, Growth Inhibition, and Cell Cycle Arrest

Molecules ◽

10.3390/molecules17067241 ◽

2012 ◽

Vol 17 (6) ◽

pp. 7241-7254 ◽

Cited By ~ 38

Author(s):

Jing-Iong Yang ◽

Chi-Chen Yeh ◽

Jin-Ching Lee ◽

Szu-Cheng Yi ◽

Hurng-Wern Huang ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Growth Inhibition ◽

Cell Cycle Arrest ◽

Aqueous Extracts ◽

Damage Growth ◽

Gracilaria Tenuistipitata ◽

Cycle Arrest

Download Full-text

Mollugin induced oxidative DNA damage via up-regulating ROS that caused cell cycle arrest in hepatoma cells

Chemico-Biological Interactions ◽

10.1016/j.cbi.2022.109805 ◽

2022 ◽

pp. 109805

Author(s):

Xin-ge Ke ◽

Yi-yi Xiong ◽

Bing Yu ◽

Chong Yuan ◽

Peng-yu Chen ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Oxidative Dna Damage ◽

Hepatoma Cells ◽

Cycle Arrest

Download Full-text

Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Chemotherapy ◽

10.1159/000491705 ◽

2018 ◽

Vol 63 (4) ◽

pp. 225-237 ◽

Cited By ~ 1

Author(s):

Haytham Khoury ◽

Ruijuan He ◽

Aaron Schimmer ◽

James R. Beadle ◽

Karl Y. Hostetler ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Acute Myeloid Leukemia ◽

Cell Cycle Arrest ◽

Clinical Benefit ◽

Myeloid Leukemia ◽

Mouse Bone Marrow ◽

Medical Needs ◽

Cycle Arrest ◽

Acute Myeloid

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50–70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipivoxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

Download Full-text