scholarly journals Dynamics of age-related catastrophic mitotic failures and recovery in yeast

2018 ◽  
Author(s):  
Matthew M. Crane ◽  
Adam E. Russell ◽  
Brent J. Schafer ◽  
Mung Gi Hong ◽  
Joslyn E. Goings ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Genomic Instability ◽  
Mother Cell ◽  
Genome Instability ◽  
Retrograde Transport ◽  
Cell Cycle Checkpoints ◽  
Control Mechanisms ◽  
Cycle Arrest ◽  
Single Cell Imaging ◽  
Age Related

AbstractGenome instability is a hallmark of aging and contributes to age-related disorders such as progeria, cancer, and Alzheimer’s disease. In particular, nuclear quality control mechanisms and cell cycle checkpoints have generally been studied in young cells and animals where they function optimally, and where genomic instability is low. Here, we use single cell imaging to study the consequences of increased genomic instability during aging, and identify striking age-associated genome missegregation events. During these events the majority of mother cell chromatin, and often both spindle poles, are mistakenly sent to the daughter cell. This breakdown in mitotic fidelity is accompanied by a transient cell cycle arrest that can persist for many hours, as cells engage a retrograde transport mechanism to return chromosomes to the mother cell. The repetitive ribosomal DNA (rDNA) has been previously identified as being highly vulnerable to age-related replication stress and genomic instability, and we present several lines of evidence supporting a model whereby expansion of rDNA during aging results in nucleolar breakdown and competition for limited nucleosomes, thereby increasing risk of catastrophic genome missegregation.

scholarly journals DNA damage checkpoint activation impairs chromatin homeostasis and promotes mitotic catastrophe during aging

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Matthew M Crane ◽  
Adam E Russell ◽  
Brent J Schafer ◽  
Ben W Blue ◽  
Riley Whalen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Instability ◽  
Cell Cycle Checkpoints ◽  
Mitotic Catastrophe ◽  
Dna Damage Checkpoint ◽  
Age Related ◽  
Altered Cell ◽  
Histone Transcription ◽  
Cell Cycle Dynamics

Genome instability is a hallmark of aging and contributes to age-related disorders such as cancer and Alzheimer’s disease. The accumulation of DNA damage during aging has been linked to altered cell cycle dynamics and the failure of cell cycle checkpoints. Here, we use single cell imaging to study the consequences of increased genomic instability during aging in budding yeast and identify striking age-associated genome missegregation events. This breakdown in mitotic fidelity results from the age-related activation of the DNA damage checkpoint and the resulting degradation of histone proteins. Disrupting the ability of cells to degrade histones in response to DNA damage increases replicative lifespan and reduces genomic missegregations. We present several lines of evidence supporting a model of antagonistic pleiotropy in the DNA damage response where histone degradation, and limited histone transcription are beneficial to respond rapidly to damage but reduce lifespan and genomic stability in the long term.

scholarly journals Cellular Senescence in Liver Disease and Regeneration

2021 ◽  
Author(s):  
Sofia Ferreira-Gonzalez ◽  
Daniel Rodrigo-Torres ◽  
Victoria L. Gadd ◽  
Stuart J. Forbes
Keyword(s):  
Cell Cycle ◽  
Liver Disease ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Cellular Senescence ◽  
Cell Populations ◽  
Cycle Arrest ◽  
Relevant Role ◽  
Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

The regulation of the DNA damage response at telomeres: focus on kinases

2021 ◽  
Author(s):  
Michela Galli ◽  
Chiara Frigerio ◽  
Maria Pia Longhese ◽  
Michela Clerici
Keyword(s):  
Cell Cycle ◽  
Cellular Response ◽  
Cell Cycle Progression ◽  
Binding Proteins ◽  
Replicative Senescence ◽  
Genome Instability ◽  
Cycle Progression ◽  
Strand Breaks ◽  
Cycle Arrest ◽  
Linear Chromosomes

The natural ends of linear chromosomes resemble those of accidental double-strand breaks (DSBs). DSBs induce a multifaceted cellular response that promotes the repair of lesions and slows down cell cycle progression. This response is not elicited at chromosome ends, which are organized in nucleoprotein structures called telomeres. Besides counteracting DSB response through specialized telomere-binding proteins, telomeres also prevent chromosome shortening. Despite of the different fate of telomeres and DSBs, many proteins involved in the DSB response also localize at telomeres and participate in telomere homeostasis. In particular, the DSB master regulators Tel1/ATM and Mec1/ATR contribute to telomere length maintenance and arrest cell cycle progression when chromosome ends shorten, thus promoting a tumor-suppressive process known as replicative senescence. During senescence, the actions of both these apical kinases and telomere-binding proteins allow checkpoint activation while bulk DNA repair activities at telomeres are still inhibited. Checkpoint-mediated cell cycle arrest also prevents further telomere erosion and deprotection that would favor chromosome rearrangements, which are known to increase cancer-associated genome instability. This review summarizes recent insights into functions and regulation of Tel1/ATM and Mec1/ATR at telomeres both in the presence and in the absence of telomerase, focusing mainly on discoveries in budding yeast.

scholarly journals PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors

2019 ◽  
Vol 116 (39) ◽  
pp. 19464-19473 ◽  
Author(s):  
Stella Pappa ◽  
Natalia Padilla ◽  
Simona Iacobucci ◽  
Marta Vicioso ◽  
Elena Álvarez de la Campa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Neural Progenitors ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Biochemical Assays

Histone H3 lysine 9 methylation (H3K9me) is essential for cellular homeostasis; however, its contribution to development is not well established. Here, we demonstrate that the H3K9me2 demethylase PHF2 is essential for neural progenitor proliferation in vitro and for early neurogenesis in the chicken spinal cord. Using genome-wide analyses and biochemical assays we show that PHF2 controls the expression of critical cell cycle progression genes, particularly those related to DNA replication, by keeping low levels of H3K9me3 at promoters. Accordingly, PHF2 depletion induces R-loop accumulation that leads to extensive DNA damage and cell cycle arrest. These data reveal a role of PHF2 as a guarantor of genome stability that allows proper expansion of neural progenitors during development.

scholarly journals Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a

Oncogene ◽  
2002 ◽  
Vol 21 (40) ◽  
pp. 6228-6233 ◽  
Author(s):  
M Christine Hollander ◽  
Albert J Fornace
Keyword(s):  
Cell Cycle ◽  
Genomic Instability ◽  
Centrosome Amplification ◽  
Cell Cycle Checkpoints

scholarly journals Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging

Oncotarget ◽  
2016 ◽  
Vol 7 (11) ◽  
pp. 11838-11849 ◽  
Author(s):  
Tongyuan Li ◽  
Xiangyu Liu ◽  
Le Jiang ◽  
James Manfredi ◽  
Shan Zha ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Premature Aging ◽  
Cycle Arrest

scholarly journals p53 protects against genome instability following centriole duplication failure

2015 ◽  
Vol 210 (1) ◽  
pp. 63-77 ◽  
Author(s):  
Bramwell G. Lambrus ◽  
Yumi Uetake ◽  
Kevin M. Clutario ◽  
Vikas Daggubati ◽  
Michael Snyder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Gene Targeting ◽  
Chromosome Segregation ◽  
De Novo ◽  
Genome Instability ◽  
Centriole Duplication ◽  
Cycle Arrest ◽  
Surveillance Mechanism

Centriole function has been difficult to study because of a lack of specific tools that allow persistent and reversible centriole depletion. Here we combined gene targeting with an auxin-inducible degradation system to achieve rapid, titratable, and reversible control of Polo-like kinase 4 (Plk4), a master regulator of centriole biogenesis. Depletion of Plk4 led to a failure of centriole duplication that produced an irreversible cell cycle arrest within a few divisions. This arrest was not a result of a prolonged mitosis, chromosome segregation errors, or cytokinesis failure. Depleting p53 allowed cells that fail centriole duplication to proliferate indefinitely. Washout of auxin and restoration of endogenous Plk4 levels in cells that lack centrioles led to the penetrant formation of de novo centrioles that gained the ability to organize microtubules and duplicate. In summary, we uncover a p53-dependent surveillance mechanism that protects against genome instability by preventing cell growth after centriole duplication failure.

scholarly journals p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Sunetra Roy ◽  
Karl-Heinz Tomaszowski ◽  
Jessica W Luzwick ◽  
Soyoung Park ◽  
Jun Li ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genomic Instability ◽  
Genome Instability ◽  
Single Cells ◽  
Replication Forks ◽  
Mutational Signatures ◽  
Development Of Resistance ◽  
Cycle Arrest ◽  
Replication Restart ◽  
Dna Replication Restart

Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks that drive genomic instability, which isgenetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53-mediated suppression of replication genome instability.

scholarly journals Getting to S: CDK functions and targets on the path to cell-cycle commitment

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2374 ◽  
Author(s):  
Robert P. Fisher
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Growth Conditions ◽  
Control Mechanisms ◽  
Cell Fates ◽  
Cycle Arrest ◽  
Distinct Cell ◽  
Cast Doubt ◽  
Multicellular Organisms

How and when eukaryotic cells make the irrevocable commitment to divide remain central questions in the cell-cycle field. Parallel studies in yeast and mammalian cells seemed to suggest analogous control mechanisms operating during the G1 phase—at Start or the restriction (R) point, respectively—to integrate nutritional and developmental signals and decide between distinct cell fates: cell-cycle arrest or exit versus irreversible commitment to a round of division. Recent work has revealed molecular mechanisms underlying this decision-making process in both yeast and mammalian cells but also cast doubt on the nature and timing of cell-cycle commitment in multicellular organisms. These studies suggest an expanded temporal window of mitogen sensing under certain growth conditions, illuminate unexpected obstacles and exit ramps on the path to full cell-cycle commitment, and raise new questions regarding the functions of cyclin-dependent kinases (CDKs) that drive G1 progression and S-phase entry.

Targeting the Cell Cycle: A New Approach to Cancer Therapy

2005 ◽  
Vol 23 (36) ◽  
pp. 9408-9421 ◽  
Author(s):  
Gary K. Schwartz ◽  
Manish A. Shah
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Tumor Cell ◽  
Critical Time ◽  
Cell Cycle Checkpoints ◽  
New Approach ◽  
Cyclin Dependent Kinases ◽  
Cycle Arrest ◽  
Induce Growth Arrest ◽  
Apoptotic Cascade

The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical parts of the cell cycle machinery are the cyclin-dependent kinases (CDKs), which, when activated, provide a means for the cell to move from one phase of the cell cycle to the next. The CDKs are regulated positively by cyclins and regulated negatively by naturally occurring CDK inhibitors (CDKIs). Cancer represents a dysregulation of the cell cycle such that cells that overexpress cyclins or do not express the CDKIs continue to undergo unregulated cell growth. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest, in fact, represents a survival mechanism that provides the tumor cell the opportunity to repair its own damaged DNA. Thus, abrogation of cell cycle checkpoints, before DNA repair is complete, can activate the apoptotic cascade, leading to cell death. Now in clinical trials are a series of targeted agents that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce growth arrest. Recent attention has also focused on these drugs as inhibitors of transcription. In addition, there are now agents that abrogate the cell cycle checkpoints at critical time points that make the tumor cell susceptible to apoptosis. An understanding of the cell cycle is critical to understanding how best to clinically develop these agents, both as single agents and in combination with chemotherapy.

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