DNA damage and cell cycle checkpoints in hyperoxic lung injury: braking to facilitate repair

2001 ◽  
Vol 281 (2) ◽  
pp. L291-L305 ◽  
Author(s):  
Michael A. O'Reilly
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genotoxic Stress ◽  
Supplemental Oxygen ◽  
Cell Cycle Checkpoints ◽  
Dna Integrity ◽  
Additional Time ◽  
Pulmonary Response ◽  
Arterial Blood ◽  
Hyperoxic Lung Injury

The beneficial use of supplemental oxygen therapies to increase arterial blood oxygen levels and reduce tissue hypoxia is offset by the knowledge that it injures and kills cells, resulting in increased morbidity and mortality. Although many studies have focused on understanding how hyperoxia kills cells, recent findings reveal that it also inhibits proliferation through activation of cell cycle checkpoints rather than through overt cytotoxicity. Cell cycle checkpoints are thought to be protective because they allow additional time for injured cells to repair damaged DNA and other essential molecules. During recovery in room air, the lung undergoes a burst of proliferation to replace injured and dead cells. Failure to terminate this proliferation has been associated with fibrosis. These observations suggest that growth-suppressive signals, which inhibit proliferation of injured cells and terminate proliferation when tissue repair has been completed, may play an important role in the pulmonary response to hyperoxia. Because DNA replication is coupled with DNA repair, activation of cell cycle checkpoints during hyperoxia may be a mechanism by which cells protect themselves from oxidant genotoxic stress. This review examines the effect of hyperoxia on DNA integrity, pulmonary cell proliferation, and cell cycle checkpoints activated by DNA damage.

scholarly journals Inactivation of mouse Hus1 results in genomic instability and impaired responses to genotoxic stress

2000 ◽  
Vol 14 (15) ◽  
pp. 1886-1898 ◽  
Author(s):  
Robert S. Weiss ◽  
Tamar Enoch ◽  
Philip Leder
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Chromosomal Abnormalities ◽  
Genotoxic Stress ◽  
Eukaryotic Cell ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Genome Damage

The eukaryotic cell cycle is overseen by regulatory mechanisms, termed checkpoints, that respond to DNA damage, mitotic spindle defects, and errors in the ordering of cell cycle events. The DNA replication and DNA damage cell cycle checkpoints of the fission yeastSchizosaccharomyces pombe require the hus1+(hydroxyurea sensitive) gene. To determine the role of the mouse homolog of hus1+ in murine development and cell cycle checkpoint function, we produced a targeted disruption of mouse Hus1. Inactivation of Hus1results in mid-gestational embryonic lethality due to widespread apoptosis and defective development of essential extra-embryonic tissues. DNA damage-inducible genes are up-regulated inHus1-deficient embryos, and primary cells fromHus1-null embryos contain increased spontaneous chromosomal abnormalities, suggesting that loss of Hus1 leads to an accumulation of genome damage. Embryonic fibroblasts lackingHus1 fail to proliferate in vitro, but inactivation ofp21 allows for the continued growth of Hus1-deficient cells.Hus1−/−p21−/−cells display a unique profile of significantly heightened sensitivity to hydroxyurea, a DNA replication inhibitor, and ultraviolet light, but only slightly increased sensitivity to ionizing radiation. Taken together, these results indicate that mouse Hus1 functions in the maintenance of genomic stability and additionally identify an evolutionarily-conserved role for Hus1 in mediating cellular responses to genotoxins.

scholarly journals Cell cycle checkpoints cooperate to suppress DNA and RNA associated molecular pattern recognition and anti-tumor immune responses

2020 ◽  
Author(s):  
Jie Chen ◽  
Shane M Harding ◽  
Ramakrishnan Natesan ◽  
Lei Tian ◽  
Joseph L Benci ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pattern Recognition ◽  
Dna Damage ◽  
Immune Responses ◽  
Genotoxic Stress ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Dna And Rna ◽  
Molecular Pattern ◽  
Immune Mediated

SummaryThe DNA dependent pattern recognition receptor, cGAS mediates communication between genotoxic stress and the immune system. Mitotic chromosome missegregation is an established stimulator of cGAS activity, however, it is unclear if progression through mitosis is required for cancer cell intrinsic activation of immune mediated anti-tumor responses. Moreover, it is unknown if disruption of cell cycle checkpoints can restore responses in cancer cells that are recalcitrant to DNA damage induced inflammation. Here we demonstrate that prolonged cell cycle arrest at the G2-mitosis boundary from either CDK1 inhibition or excessive DNA damage prevents inflammatory stimulated gene expression and immune mediated destruction of distal tumors. Remarkably, DNA damage induced inflammatory signaling is restored in a cGAS-and RIG-I-dependent manner upon concomitant disruption of p53 and the G2 checkpoint. These findings link aberrant cell progression and p53 loss to an expanded spectrum of damage associated molecular pattern recognition and have implications for the design of rational approaches to augment antitumor immune responses.

scholarly journals DNA Damage and L1 Retrotransposition

2006 ◽  
Vol 2006 ◽  
pp. 1-8 ◽  
Author(s):  
Evan A. Farkash ◽  
Eline T. Luning Prak
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Instability ◽  
Genotoxic Stress ◽  
Severe Form ◽  
Cell Cycle Checkpoints ◽  
Dna Breaks ◽  
Double Stranded Dna ◽  
Barbara Mcclintock ◽  
L1 Element

Barbara McClintock was the first to suggest that transposons are a source of genome instability and that genotoxic stress assisted in their mobilization. The generation of double-stranded DNA breaks (DSBs) is a severe form of genotoxic stress that threatens the integrity of the genome, activates cell cycle checkpoints, and, in some cases, causes cell death. Applying McClintock's stress hypothesis to humans, are L1 retrotransposons, the most active autonomous mobile elements in the modern day human genome, mobilized by DSBs? Here, evidence that transposable elements, particularly retrotransposons, are mobilized by genotoxic stress is reviewed. In the setting of DSB formation, L1 mobility may be affected by changes in the substrate for L1 integration, the DNA repair machinery, or the L1 element itself. The review concludes with a discussion of the potential consequences of L1 mobilization in the setting of genotoxic stress.

scholarly journals Human TopBP1 Ensures Genome Integrity during Normal S Phase

2005 ◽  
Vol 25 (24) ◽  
pp. 10907-10915 ◽  
Author(s):  
Ja-Eun Kim ◽  
Sarah A. McAvoy ◽  
David I. Smith ◽  
Junjie Chen
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Critical Role ◽  
Genotoxic Stress ◽  
S Phase ◽  
Fragile Sites ◽  
Cell Cycle Checkpoints ◽  
Exogenous Dna ◽  
Hydroxyurea Treatment

ABSTRACT Cell cycle checkpoints are essential for maintaining genomic integrity. Human topoisomerase II binding protein 1 (TopBP1) shares sequence similarity with budding yeast Dpb11, fission yeast Rad4/Cut5, and Xenopus Cut5, all of which are required for DNA replication and cell cycle checkpoints. Indeed, we have shown that human TopBP1 participates in the activation of replication checkpoint and DNA damage checkpoints, following hydroxyurea treatment and ionizing radiation. In this study, we address the physiological function of TopBP1 in S phase by using small interfering RNA. In the absence of exogenous DNA damage, TopBP1 is recruited to replicating chromatin. However, TopBP1 does not appear to be essential for DNA replication. TopBP1-deficient cells have increased H2AX phosphorylation and ATM-Chk 2 activation, suggesting the accumulation of DNA double-strand breaks in the absence of TopBP1. This leads to formation of gaps and breaks at fragile sites, 4N accumulation, and aberrant cell division. We propose that the cellular function of TopBP1 is to monitor ongoing DNA replication. By ensuring proper DNA replication, TopBP1 plays a critical role in the maintenance of genomic stability during normal S phase as well as following genotoxic stress.

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

scholarly journals Cell Cycle and DNA Repair Regulation in the Damage Response: Protein Phosphatases Take Over the Reins

2020 ◽  
Vol 21 (2) ◽  
pp. 446 ◽  
Author(s):  
Adrián Campos ◽  
Andrés Clemente-Blanco
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Protein Phosphatases ◽  
Genetic Material ◽  
Protein Composition ◽  
Genotoxic Stress ◽  
Damage Response ◽  
Protein Dephosphorylation

Cells are constantly suffering genotoxic stresses that affect the integrity of our genetic material. Genotoxic insults must be repaired to avoid the loss or inappropriate transmission of the genetic information, a situation that could lead to the appearance of developmental abnormalities and tumorigenesis. To combat this threat, eukaryotic cells have evolved a set of sophisticated molecular mechanisms that are collectively known as the DNA damage response (DDR). This surveillance system controls several aspects of the cellular response, including the detection of lesions, a temporary cell cycle arrest, and the repair of the broken DNA. While the regulation of the DDR by numerous kinases has been well documented over the last decade, the complex roles of protein dephosphorylation have only recently begun to be investigated. Here, we review recent progress in the characterization of DDR-related protein phosphatases during the response to a DNA lesion, focusing mainly on their ability to modulate the DNA damage checkpoint and the repair of the damaged DNA. We also discuss their protein composition and structure, target specificity, and biochemical regulation along the different stages encompassed in the DDR. The compilation of this information will allow us to better comprehend the physiological significance of protein dephosphorylation in the maintenance of genome integrity and cell viability in response to genotoxic stress.

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