scholarly journals Measuring cell cycle-dependent DNA damage responses and p53 regulation on a cell-by-cell basis from image analysis

Cell Cycle ◽  
2018 ◽  
Vol 17 (11) ◽  
pp. 1358-1371 ◽  
Author(s):  
Shivnarayan Dhuppar ◽  
Aprotim Mazumder
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Image Analysis ◽  
Measuring Cell ◽  
Cell Basis ◽  
Dna Damage Responses ◽  
A Cell ◽  
Cycle Dependent

A Role for NIPA in DNA Damage Response.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1265-1265
Author(s):  
Christine von Klitzing ◽  
Florian Bassermann ◽  
Stephan W. Morris ◽  
Christian Peschel ◽  
Justus Duyster
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Phosphorylation Site ◽  
Genotoxic Stress ◽  
S Phase ◽  
Damage Response ◽  
A Cell ◽  
Cycle Dependent

Abstract The nuclear interaction partner of ALK (NIPA) is a nuclear protein identified by our group in a screen for NPM-ALK interaction partners. We recently reported that NIPA is an F-box protein that assembles with SKP1, Cul1 and Roc1 to establish a novel SCF-type E3 ubiquitin ligase. The formation of the SCFNIPA complex is regulated by cell cycle-dependent phosphorylation of NIPA that restricts SCFNIPA assembly from G1- to late S-phase, thus allowing its substrates to be active from late S-phase throughout mitosis. Proteins involved in cell cycle regulation frequently play a role in DNA damage checkpoints. We therefore sought to determine whether NIPA has a function in the cellular response to genotoxic stress. For this reason we treated NIH/3T3 cells with various DNA-damaging agents. Surprisingly, we observed phosphorylation of NIPA in response to some of these agents, including UV radiation. This phosphorylation was cell cycle phase independent and thus independent of the physiological cell cycle dependent phosphorylation of NIPA. The relevant phosphorylation site is identical to the respective site in the course of cell cycle-dependent phosphorylation of NIPA. Thus, phosphorylation of NIPA upon genotoxic stress would inactivate the SCFNIPA complex in a cell cycle independent manner. Interestingly, this phosphorylation site lies within a consensus site of the Chk1/Chk2 checkpoint kinases. These kinases are central to DNA damage checkpoint signaling. Chk1 is activated by ATR in response to blocked replication forks as they occur after treatment with UV. We performed experiments using the ATM/ATR inhibitor caffeine and the Chk1 inhibitor SB218078 to investigate a potential role of Chk1 in NIPA phosphorylation. Indeed, we found both inhibitors to prevent UV-induced phosphorylation of NIPA. Current experiments applying Chk1 knock-out cells will unravel the role of Chk1 in NIPA phosphorylation. Additional experiments were performed to investigate a function for NIPA in DNA-damage induced apoptosis. In this regard, we observed overexpression of NIPA WT to induce apoptosis in response to UV, whereas no proapoptotic effect was seen with the phosphorylation deficient NIPA mutant. Therefore, the phosphorylated form of NIPA may be involved in apoptotic signaling pathways. In summary, we present data suggesting a cell cycle independent function for NIPA. This activity is involved in DNA damage response and may be involved in regulating apoptosis upon genotoxic stress.

scholarly journals Dynamic Alterations of Histone H3 Phospho-acetylation Correlate With Radio Sensitivity of Mitotic Cells During DNA Damage

2020 ◽  
Author(s):  
Asmita Sharda ◽  
Tripti Verma ◽  
Nikhil Gadewal ◽  
Sanjay Gupta
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Cycle Progression ◽  
Protein Translation ◽  
Chemotherapeutic Agents ◽  
Open Chromatin ◽  
Dependent Manner ◽  
A Cell ◽  
Cycle Dependent

Abstract Background - Histone Post Translational Modifications (PTMs) change in a cell cycle dependent manner and also orchestrate the DNA repair process for radiation induced DNA damage. Mitosis is the most radiosensitive phase of the cell cycle but the epigenetic events that regulate its radiosensitivity remain elusive.Results - This study explored the dynamics between histone marks H3S10/S28ph, H3K9ac and γH2AX during mitotic DNA damage response. The presence of a mononucleosome level association between γH2AX and H3S10ph was observed only during mitosis. This association was abrogated upon cell cycle progression and chromatin de-condensation, concomitant with chromatin recruitment of DNA repair proteins Ku70 and Rad51. Moreover, the levels of H3S10/28ph remained unchanged upon DNA damage during mitosis, but decreased in a cell cycle dependent manner upon mitotic exit. However, the population that arose after mitotic progression of damaged cells comprised of binucleated tetraploid cells. This population was epigenetically distinct from interphase cells, characterized by reduced H3S10/S28ph, increased H3K9ac and more open chromatin configuration. These epigenetic features correlated with decreased survival potential of this population. The low levels of H3S10/28ph were attributed to decreased protein translation and chromatin recruitment of histone kinase Mitogen and Stress-activated Kinase 1 (MSK1) along with persistent levels of Protein phosphatase1 catalytic subunit α (PP1α). Conclusions – This study suggests that a unique epigenetic landscape attained during and after mitotic DNA damage collectively contributed to mitotic radiosensitivity. The findings of this study have potential clinical significance in terms of tackling resistance against anti-mitotic chemotherapeutic agents.

scholarly journals Topoisomerase IIα prevents ultrafine anaphase bridges by two mechanisms

Open Biology ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 190259
Author(s):  
Simon Gemble ◽  
Géraldine Buhagiar-Labarchède ◽  
Rosine Onclercq-Delic ◽  
Gaëlle Fontaine ◽  
Sarah Lambert ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Free Resolution ◽  
Cycle Phase ◽  
Dependent Manner ◽  
Topoisomerase Iiα ◽  
Anaphase Bridges ◽  
A Cell ◽  
Cycle Dependent

Topoisomerase IIα (Topo IIα), a well-conserved double-stranded DNA (dsDNA)-specific decatenase, processes dsDNA catenanes resulting from DNA replication during mitosis. Topo IIα defects lead to an accumulation of ultrafine anaphase bridges (UFBs), a type of chromosome non-disjunction. Topo IIα has been reported to resolve DNA anaphase threads, possibly accounting for the increase in UFB frequency upon Topo IIα inhibition. We hypothesized that the excess UFBs might also result, at least in part, from an impairment of the prevention of UFB formation by Topo IIα. We found that Topo IIα inhibition promotes UFB formation without affecting the global disappearance of UFBs during mitosis, but leads to an aberrant UFB resolution generating DNA damage within the next G1. Moreover, we demonstrated that Topo IIα inhibition promotes the formation of two types of UFBs depending on cell cycle phase. Topo IIα inhibition during S-phase compromises complete DNA replication, leading to the formation of UFB-containing unreplicated DNA, whereas Topo IIα inhibition during mitosis impedes DNA decatenation at metaphase–anaphase transition, leading to the formation of UFB-containing DNA catenanes. Thus, Topo IIα activity is essential to prevent UFB formation in a cell-cycle-dependent manner and to promote DNA damage-free resolution of UFBs.

scholarly journals CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner

Cell Cycle ◽  
2018 ◽  
Vol 17 (12) ◽  
pp. 1513-1523 ◽  
Author(s):  
Remko Prevo ◽  
Giacomo Pirovano ◽  
Rathi Puliyadi ◽  
Katharine J. Herbert ◽  
Gonzalo Rodriguez-Berriguete ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dependent Manner ◽  
Normal Cells ◽  
A Cell ◽  
Cycle Dependent

scholarly journals Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4

2010 ◽  
Vol 29 (18) ◽  
pp. 3130-3139 ◽  
Author(s):  
Sophie E Polo ◽  
Abderrahmane Kaidi ◽  
Linda Baskcomb ◽  
Yaron Galanty ◽  
Stephen P Jackson
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Chromatin Remodelling ◽  
Cycle Progression ◽  
Dna Damage Responses

scholarly journals Truncated APC regulates the transcriptional activity of β-catenin in a cell cycle dependent manner

2006 ◽  
Vol 16 (2) ◽  
pp. 199-209 ◽  
Author(s):  
Jean Schneikert ◽  
Annette Grohmann ◽  
Jürgen Behrens
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activity ◽  
Dependent Manner ◽  
A Cell ◽  
Cycle Dependent

scholarly journals Effects of cell-cycle-dependent expression on random fluctuations in protein levels

2016 ◽  
Vol 3 (12) ◽  
pp. 160578 ◽  
Author(s):  
Mohammad Soltani ◽  
Abhyudai Singh
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Protein Levels ◽  
Stochastic Component ◽  
Stochastic Expression ◽  
A Cell ◽  
Intrinsic Stochasticity ◽  
Cycle Dependent ◽  
Random Fluctuations ◽  
Cell To Cell Variability

Expression of many genes varies as a cell transitions through different cell-cycle stages. How coupling between stochastic expression and cell cycle impacts cell-to-cell variability (noise) in the level of protein is not well understood. We analyse a model where a stable protein is synthesized in random bursts, and the frequency with which bursts occur varies within the cell cycle. Formulae quantifying the extent of fluctuations in the protein copy number are derived and decomposed into components arising from the cell cycle and stochastic processes. The latter stochastic component represents contributions from bursty expression and errors incurred during partitioning of molecules between daughter cells. These formulae reveal an interesting trade-off: cell-cycle dependencies that amplify the noise contribution from bursty expression also attenuate the contribution from partitioning errors. We investigate the existence of optimum strategies for coupling expression to the cell cycle that minimize the stochastic component. Intriguingly, results show that a zero production rate throughout the cell cycle, with expression only occurring just before cell division, minimizes noise from bursty expression for a fixed mean protein level. By contrast, the optimal strategy in the case of partitioning errors is to make the protein just after cell division. We provide examples of regulatory proteins that are expressed only towards the end of the cell cycle, and argue that such strategies enhance robustness of cell-cycle decisions to the intrinsic stochasticity of gene expression.

scholarly journals Differentiating life and death: An inflammatory affair

2018 ◽  
Author(s):  
Dustin Lane
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Differentiation ◽  
Programmed Cell Death ◽  
Signaling Networks ◽  
Inhibitors Of Apoptosis ◽  
Life And Death ◽  
Cell Death Signaling ◽  
Cycle Dependent

Programmed cell death signaling networks are frequently activated to coordinate the process of cell differentiation, and a variety of apoptotic events can mediate the process. This can include the ligation of death receptors, the activation of downstream caspases, and the induction of chromatin fragmentation, and all of these events can occur without downstream induction of death. Importantly, regulators of programmed cell death also have established roles in mediating differentiation. This review will provide an overview of apoptosis and its regulation by Inhibitors of Apoptosis (IAPs) and Bcl-2 family members. It will then outline the cross-talk between NF-ĸB and apoptotic signaling in the regulation of apoptosis before discussing the function of these regulators in the control of cell differentiation. It will end on a discussion of how a DNA damage-directed, cell cycle-dependent differentiation program may be controlled across multiple passages through cell cycle, and will assert that the failure to properly differentiate is the underlying cause of cancer.

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