Genome-wide survey of protein kinases required for cell cycle progression

Nature ◽  
2004 ◽  
Vol 432 (7020) ◽  
pp. 980-987 ◽  
Author(s):  
M. Bettencourt-Dias ◽  
R. Giet ◽  
R. Sinka ◽  
A. Mazumdar ◽  
W. G. Lock ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinases ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Genome Wide ◽  
Genome Wide Survey

scholarly journals Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

Open Biology ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 140156 ◽  
Author(s):  
Didier J. Colin ◽  
Karolina O. Hain ◽  
Lindsey A. Allan ◽  
Paul R. Clarke
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinases ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Anti Cancer ◽  
Damage Response ◽  
Microtubule Poisons

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

scholarly journals p50 mono-ubiquitination and interaction with BARD1 regulates cell cycle progression and maintains genome stability

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Longtao Wu ◽  
Clayton D. Crawley ◽  
Andrea Garofalo ◽  
Jackie W. Nichols ◽  
Paige-Ashley Campbell ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Human Cancer ◽  
S Phase ◽  
Post Translational Modification ◽  
Chromosomal Breakage ◽  
Cycle Progression ◽  
Genome Wide ◽  
Phase Progression

Abstract p50, the mature product of NFKB1, is constitutively produced from its precursor, p105. Here, we identify BARD1 as a p50-interacting factor. p50 directly associates with the BARD1 BRCT domains via a C-terminal phospho-serine motif. This interaction is induced by ATR and results in mono-ubiquitination of p50 by the BARD1/BRCA1 complex. During the cell cycle, p50 is mono-ubiquitinated in S phase and loss of this post-translational modification increases S phase progression and chromosomal breakage. Genome-wide studies reveal a substantial decrease in p50 chromatin enrichment in S phase and Cycln E is identified as a factor regulated by p50 during the G1 to S transition. Functionally, interaction with BARD1 promotes p50 protein stability and consistent with this, in human cancer specimens, low nuclear BARD1 protein strongly correlates with low nuclear p50. These data indicate that p50 mono-ubiquitination by BARD1/BRCA1 during the cell cycle regulates S phase progression to maintain genome integrity.

scholarly journals A genome-wide resource of cell cycle and cell shape genes of fission yeast

Open Biology ◽  
2013 ◽  
Vol 3 (5) ◽  
pp. 130053 ◽  
Author(s):  
Jacqueline Hayles ◽  
Valerie Wood ◽  
Linda Jeffery ◽  
Kwang-Lae Hoe ◽  
Dong-Uk Kim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Fission Yeast ◽  
Cell Shape ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Gene Deletions ◽  
Genome Wide ◽  
A Genome ◽  
Protein Encoding ◽  
Encoding Genes

To identify near complete sets of genes required for the cell cycle and cell shape, we have visually screened a genome-wide gene deletion library of 4843 fission yeast deletion mutants (95.7% of total protein encoding genes) for their effects on these processes. A total of 513 genes have been identified as being required for cell cycle progression, 276 of which have not been previously described as cell cycle genes. Deletions of a further 333 genes lead to specific alterations in cell shape and another 524 genes result in generally misshapen cells. Here, we provide the first eukaryotic resource of gene deletions, which describes a near genome-wide set of genes required for the cell cycle and cell shape.

scholarly journals Genome-wide profiling of nardilysin target genes reveals its role in epigenetic regulation and cell cycle progression

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Yusuke Morita ◽  
Mikiko Ohno ◽  
Kiyoto Nishi ◽  
Yoshinori Hiraoka ◽  
Sayaka Saijo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Epigenetic Regulation ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Cycle Progression ◽  
Genome Wide

scholarly journals GATA-2 Reinforces Megakaryocyte Development in the Absence of GATA-1

2009 ◽  
Vol 29 (18) ◽  
pp. 5168-5180 ◽  
Author(s):  
Zan Huang ◽  
Louis C. Dore ◽  
Zhe Li ◽  
Stuart H. Orkin ◽  
Gang Feng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Regulators ◽  
Cycle Progression ◽  
Megakaryoblastic Leukemia ◽  
Genome Wide ◽  
Expression Program ◽  
Mutant Cells ◽  
Leukemia In Children ◽  
Essential Transcription Factor

ABSTRACTGATA-2 is an essential transcription factor that regulates multiple aspects of hematopoiesis. Dysregulation of GATA-2 is a hallmark of acute megakaryoblastic leukemia in children with Down syndrome, a malignancy that is defined by the combination of trisomy 21 and aGATA1mutation. Here, we show that GATA-2 is required for normal megakaryocyte development as well as aberrant megakaryopoiesis inGata1mutant cells. Furthermore, we demonstrate that GATA-2 indirectly controls cell cycle progression in GATA-1-deficient megakaryocytes. Genome-wide microarray analysis and chromatin immunoprecipitation studies revealed that GATA-2 regulates a wide set of genes, including cell cycle regulators and megakaryocyte-specific genes. Surprisingly, GATA-2 also negatively regulates the expression of crucial myeloid transcription factors, such asSfpi1andCebpa. In the absence of GATA-1, GATA-2 prevents induction of a latent myeloid gene expression program. Thus, GATA-2 contributes to cell cycle progression and the maintenance of megakaryocyte identity of GATA-1-deficient cells, including GATA-1s-expressing fetal megakaryocyte progenitors. Moreover, our data reveal that overexpression of GATA-2 facilitates aberrant megakaryopoiesis.

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