scholarly journals Modelling the checkpoint response to telomere uncapping in budding yeast

2006 ◽  
Vol 4 (12) ◽  
pp. 73-90 ◽  
Author(s):  
C.J Proctor ◽  
D.A Lydall ◽  
R.J Boys ◽  
C.S Gillespie ◽  
D.P Shanley ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Time Course ◽  
Budding Yeast ◽  
Checkpoint Proteins ◽  
Cycle Arrest ◽  
Damage Response

One of the DNA damage-response mechanisms in budding yeast is temporary cell-cycle arrest while DNA repair takes place. The DNA damage response requires the coordinated interaction between DNA repair and checkpoint pathways. Telomeres of budding yeast are capped by the Cdc13 complex. In the temperature-sensitive cdc13-1 strain, telomeres are unprotected over a specific temperature range leading to activation of the DNA damage response and subsequently cell-cycle arrest. Inactivation of cdc13-1 results in the generation of long regions of single-stranded DNA (ssDNA) and is affected by the activity of various checkpoint proteins and nucleases. This paper describes a mathematical model of how uncapped telomeres in budding yeast initiate the checkpoint pathway leading to cell-cycle arrest. The model was encoded in the Systems Biology Markup Language (SBML) and simulated using the stochastic simulation system Biology of Ageing e-Science Integration and Simulation (BASIS). Each simulation follows the time course of one mother cell keeping track of the number of cell divisions, the level of activity of each of the checkpoint proteins, the activity of nucleases and the amount of ssDNA generated. The model can be used to carry out a variety of in silico experiments in which different genes are knocked out and the results of simulation are compared to experimental data. Possible extensions to the model are also discussed.

High NaCl causes Mre11 to leave the nucleus, disrupting DNA damage signaling and repair

2003 ◽  
Vol 285 (2) ◽  
pp. F266-F274 ◽  
Author(s):  
Natalia I. Dmitrieva ◽  
Dmitry V. Bulavin ◽  
Maurice B. Burg
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Cycle Arrest ◽  
Damage Response

High NaCl causes DNA double-strand breaks and cell cycle arrest, but the mechanism of its genotoxicity has been unclear. In this study, we describe a novel mechanism that contributes to this genotoxicity. The Mre11 exonuclease complex is a central component of DNA damage response. This complex assembles at sites of DNA damage, where it processes DNA ends for subsequent activation of repair and initiates cell cycle checkpoints. However, this does not occur with DNA damage caused by high NaCl. Rather, following high NaCl, Mre11 exits from the nucleus, DNA double-strand breaks accumulate in the S and G2 phases of the cell cycle, and DNA repair is inhibited. Furthermore, the exclusion of Mre11 from the nucleus by high NaCl persists following UV or ionizing radiation, also preventing DNA repair in response to those stresses, as evidenced by absence of H2AX phosphorylation at places of DNA damage and by impaired repair of damaged reporter plasmids. Activation of chk1 by phosphorylation on Ser345 generally is required for DNA damage-induced cell cycle arrest. However, chk1 does not become phosphorylated during high NaCl-induced cell cycle arrest. Also, high NaCl prevents ionizing and UV radiation-induced phosphorylation of chk1, but cell cycle arrest still occurs, indicating the existence of alternative mechanisms for the S and G2/M delays. DNA breaks that occur normally during processes such as DNA replication and transcription, as well as damages to DNA induced by genotoxic stresses, ordinarily are rapidly repaired. We propose that inhibition of this repair by high NaCl results in accumulation of DNA damage, accounting for the genotoxicity of high NaCl, and that cell cycle delay induced by high NaCl slows accumulation of DNA damage until the DNA damage-response network can be reactivated.

scholarly journals RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Toshinori Ozaki ◽  
Akira Nakagawara ◽  
Hiroki Nagase
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Apoptotic Cell Death ◽  
Cycle Arrest ◽  
Damage Response

A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

scholarly journals Inhibition of p53 improves CRISPR/Cas - mediated precision genome editing

2017 ◽  
Author(s):  
Emma Haapaniemi ◽  
Sandeep Botla ◽  
Jenna Persson ◽  
Bernhard Schmierer ◽  
Jussi Taipale
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Cell Cycle Arrest ◽  
Genome Editing ◽  
Dna Damage Response ◽  
Normal Cells ◽  
Cycle Arrest ◽  
Damage Response

AbstractWe report here that genome editing by CRISPR/Cas9 induces a p53-mediated DNA damage response and cell cycle arrest. Transient inhibition of p53 prevents this response, and increases the rate of homologous recombination more than five-fold. This provides a way to improve precision genome editing of normal cells, but warrants caution in using CRISPR for human therapies until the mechanism of the activation of p53 is elucidated.

scholarly journals The Oxygen-Rich Postnatal Environment Induces Cardiomyocyte Cell-Cycle Arrest through DNA Damage Response

Cell ◽  
2014 ◽  
Vol 157 (3) ◽  
pp. 565-579 ◽  
Author(s):  
Bao N. Puente ◽  
Wataru Kimura ◽  
Shalini A. Muralidhar ◽  
Jesung Moon ◽  
James F. Amatruda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Cycle Arrest ◽  
Damage Response ◽  
Postnatal Environment

scholarly journals ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 845
Author(s):  
Liem Minh Phan ◽  
Abdol-Hossein Rezaeian
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Signaling Pathways ◽  
Dna Damage Response ◽  
Cancer Development ◽  
Cellular Processes ◽  
Cycle Arrest ◽  
Damage Response ◽  
Cancer Cell Survival

ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative sensing, among others. Of note, ATM is often considered a major tumor suppressor because of its ability to induce apoptosis and cell cycle arrest. However, in some advanced stage tumor cells, ATM signaling is increased and confers remarkable advantages for cancer cell survival, resistance to radiation and chemotherapy, biosynthesis, proliferation, and metastasis. This review focuses on addressing major characteristics, signaling pathways and especially the diverse roles of ATM in cellular homeostasis and cancer development.

scholarly journals What Lies in between Telomere and Organismal Ageing: Comparison between Replicative Senescence and Stress-Induced Premature Senescence

2021 ◽  
Vol 245 ◽  
pp. 03051
Author(s):  
Hanyi Jia
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Replicative Senescence ◽  
Premature Senescence ◽  
Cycle Arrest ◽  
Damage Response ◽  
Permanent Cell ◽  
Stress Induced Premature Senescence

A mitotic cell that rests in permanent cell cycle arrest without the ability to divide is considered as a senescent cell. Cellular senescence is essential to limit the function of cells with heavy DNA damages. The lack of senescence is in favour of tumorigenesis, whereas the accumulation of senescent cells in tissues is likely to induce ageing and age-related pathologies on the organismal level. Understanding of cellular senescence is thus critical to both cancer and ageing studies. Senescence, essentially permanent cell cycle arrest, is one of the results of DNA damage response, such as the ataxia telangiectasia mutated and the ataxia telangiectasia and Rad3-related signaling pathways. In other cases, mild DNA damages can usually be repaired after DNA damage response, while the cells with heavy damages on DNA end in apoptosis. The damage to the special structure of telomere, however, prone to result in permanent cell cycle arrest after activation of DNA damage response. In fact, a few previous pieces of research on ageing have largely focused on telomere and considered it a primary contributor to different types of senescence. For instance, its reduction in length after each replication turns on a timer for replicative senescence, and its tandem repeats specific to binding proteins makes it susceptible to DNA damage from oxidative stress, and thus stress-induced premature senescence. In most of the senescent cells, the accumulation of biomarkers is found around the telomere which has either its tail structure disassembled or damage foci exposed on the tandem repeats. In this review, among several types of senescence, I will investigate two of the most common and widely discussed types in eukaryotic cells -replicative senescence and stress-induced premature senescence - in terms of their mechanism, relationship with telomere, and implication to organismal ageing.

scholarly journals Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation

Blood ◽  
2015 ◽  
Vol 126 (12) ◽  
pp. 1473-1482 ◽  
Author(s):  
Diamantis G. Konstantinidis ◽  
Katie M. Giger ◽  
Mary Risinger ◽  
Suvarnamala Pushkaran ◽  
Ping Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Deficient Mouse ◽  
Cycle Arrest ◽  
Rhoa Gtpase ◽  
Key Points ◽  
Damage Response ◽  
P53 Activation

Key Points RhoA GTPase activates pMRLC and localizes to the site of midbody formation to regulate erythroblast cytokinesis. Cytokinesis failure in erythroblasts caused by RhoA deficiency triggers p53-mediated DNA-damage response, cell-cycle arrest, and apoptosis.

Sign in / Sign up

Export Citation Format

Share Document