Targeted Destruction of DNA Replication Protein Cdc6 by Cell Death Pathways in Mammals and Yeast

Blanchard, Frédéric; Rusiniak, Michael E.; Sharma, Karuna; Sun, Xiaolei; Todorov, Ivan; Castellano, M. Mar; Gutiérrez, Crisanto; Baumann, Heinz; Burhans, William C.

doi:10.1091/mbc.02-02-0010

Cited by 75 publications

(64 citation statements)

References 57 publications

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“…Also down-regulated by carboplatin in sensitive cells was CDC6, which is essential for the initiation of DNA replication. The protein encoded by CDC6 functions as a regulator at the early stages of DNA replication and is rapidly destroyed in cells undergoing apoptosis (41). Finally, RRM2 overexpression is associated with gemcitabine chemoresistance in pancreatic adenocarcinoma cells; in addition, that suppression of RRM2 expression by small interfering RNA enhanced gemcitabine-induced cytotoxicity in vitro has been shown to result in markedly suppressed tumor growth, increased tumor apoptosis, and inhibition of metastasis (42).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells

Peters

Freund

Ochs

2005

Molecular Cancer Therapeutics

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We have recently described an ex vivo chemoresponse assay for determining chemosensitivity in primary cultures of human tumors. In this study, we have extended these experiments in an effort to correlate chemoresponse data with gene expression patterns at the level of transcription. Primary cultures of cells derived from ovarian carcinomas of individual patients (n = 6) were characterized using the ChemoFx assay and classified as either carboplatin sensitive (n = 3) or resistant (n = 3). Three representative cultures of cells from each individual tumor were then subjected to Affymetrix gene chip analysis (n = 18) using U95A human gene chip arrays. Data were analyzed using the dCHIP software package. We identified a significant number of genes whose expression patterns were altered between carboplatin chemosensitive and chemoresistant cells, in normal culture conditions and in the presence of carboplatin for either 2 or 72 hours. Among these differentially expressed genes, we found a significant proportion to be associated with apoptosis, cell-cell communication, cell adhesion, DNA repair, and cell proliferation. In general, the molecular phenotype displayed by chemoresistant cells was reflective of an extended life span in culture in the presence of carboplatin and the genes that define this phenotype are potential biomarkers for the prognostic management of ovarian cancer patients.

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Section: Discussionmentioning

confidence: 99%

Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells

Peters

Freund

Ochs

2005

Molecular Cancer Therapeutics

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“…These cells exhibit many features of apoptosis, including chromatin condensation and nuclear DNA fragmentation at restrictive temperature (Madeo et al 1999). Programmed cell death induced by DNA damage has also been reported in yeast cells bearing mutation in the cdc6, orc2, cdc18, and dfp1 genes (Blanchard et al 2002;Qi et al 2003;Weinberger et al 2005).…”

Section: Discussionmentioning

confidence: 91%

Activation of Checkpoint Kinase Chk1 by Reactive Oxygen Species Resulting from Disruption of wat1/pop3 in Schizosaccharomyces pombe

Ahamad¹,

Verma

Ahmed

2016

Genetics

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DNA double-strand breaks are critical lesions that can lead to chromosomal aberrations and genomic instability. In response to DNA damage, Chk1, a serine/threonine kinase, is responsible for cell cycle arrest to prevent damaged cells from progressing through the cell cycle. Here, we report that the disruption of wat1, a WD repeat-containing protein, leads to the phosphorylation of Chk1. The double-deletion of chk1 and wat1 had a grave effect on the survival of fission yeast cells, and the spontaneous recombination rate was also high upon double-deletion of wat1 and chk1, as compared to the single-mutant. In the absence of wat1, the cells exhibited a high level of nuclear fragmentation that resulted in the accumulation of Rad22 yellow fluorescent protein foci. Furthermore, we show that wat1 is required for the regulation of the oxidative stress response. We observed elevated levels of reactive oxygen species (ROS) generation in wat1-null mutant that led to a high degree of propidium iodide staining at nonpermissive temperature. Based on the results presented here, we hypothesize that ROS production in wat1-null mutant cells generates DNA fragmentation that could trigger a checkpoint response and that, in the absence of checkpoint kinase Chk1, the cells exhibit severe growth defects leading to a synthetic lethal phenotype.

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“…Moreover, apoptosis induced by a variety of stimuli coincides with the destruction of Cdc6 (Blanchard et al, 2002). The destruction of Cdc6 appears to have a causal role in apoptosis, because stable Cdc6 mutants that cannot be cleaved by caspases inhibit apoptosis (Pelizon et al, 2002), perhaps by inhibiting the production of a caspase cleavage fragment of Cdc6 that has dominant-negative effects on Cdc6 function (Yim et al, 2003).…”

Section: Regulation Of Orc1 Activities During Cell Proliferationmentioning

confidence: 99%

Ubiquitylation, phosphorylation and Orc2 modulate the subcellular location of Orc1 and prevent it from inducing apoptosis

Saha

Ghosh

Vassilev

et al. 2006

Journal of Cell Science

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Previous studies have suggested that the activity of the mammalian origin recognition complex (ORC) is regulated by cell-cycle-dependent changes in its Orc1 subunit. Here, we show that Orc1 modifications such as mono-ubiquitylation and hyperphosphorylation that occur normally during S and G2-M phases, respectively, can cause Orc1 to accumulate in the cytoplasm. This would suppress reassembly of pre-replication complexes until mitosis is complete. In the absence of these modifications, transient expression of Orc1 rapidly induced p53-independent apoptosis, and Orc1 accumulated perinuclearly rather than uniformly throughout the nucleus. This behavior mimicked the increased concentration and perinuclear accumulation of endogenous Orc1 in apoptotic cells that arise spontaneously in proliferating cell cultures. Remarkably, expression of Orc1 in the presence of an equivalent amount of Orc2, the only ORC subunit that did not induce apoptosis, prevented induction of apoptosis and restored uniform nuclear localization of Orc1. This would promote assembly of ORC-chromatin sites, such as occurs during the transition from M to G1 phase. These results provide direct evidence in support of the regulatory role proposed for Orc1, and suggest that aberrant DNA replication during mammalian development could result in apoptosis through the appearance of `unmodified' Orc1.

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Targeted Destruction of DNA Replication Protein Cdc6 by Cell Death Pathways in Mammals and Yeast

Cited by 75 publications

References 57 publications

Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells

Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells

Activation of Checkpoint Kinase Chk1 by Reactive Oxygen Species Resulting from Disruption of wat1/pop3 in Schizosaccharomyces pombe

Ubiquitylation, phosphorylation and Orc2 modulate the subcellular location of Orc1 and prevent it from inducing apoptosis

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