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 Histone H1 of Trypanosoma cruzi Is Concentrated in the Nucleolus Region and Disperses upon Phosphorylation during Progression to Mitosis

2008 ◽  
Vol 7 (4) ◽  
pp. 560-568 ◽  
Author(s):  
Luciana M. Gutiyama ◽  
Julia P. Chagas da Cunha ◽  
Sergio Schenkman
Keyword(s):  
Cell Cycle ◽  
Trypanosoma Cruzi ◽  
Cell Cycle Progression ◽  
Histone H1 ◽  
Nuclear Space ◽  
Dependent Manner ◽  
Central Regions ◽  
Core Histones ◽  
A Cell ◽  
Cycle Dependent

ABSTRACT Phosphorylation of histone H1 is intimately related to the cell cycle progression in higher eukaryotes, reaching maximum levels during mitosis. We have previously shown that in the flagellated protozoan Trypanosoma cruzi, which does not condense chromatin during mitosis, histone H1 is phosphorylated at a single cyclin-dependent kinase site. By using an antibody that recognizes specifically the phosphorylated T. cruzi histone H1 site, we have now confirmed that T. cruzi histone H1 is also phosphorylated in a cell cycle-dependent manner. Differently from core histones, the bulk of nonphosphorylated histone H1 in G1 and S phases of the cell cycle is concentrated in the central regions of the nucleus, which contains the nucleolus and less densely packed chromatin. When cells pass G2, histone H1 becomes phosphorylated and starts to diffuse. At the onset of mitosis, histone H1 phosphorylation is maximal and found in the entire nuclear space. As permeabilized parasites preferentially lose phosphorylated histone H1, we conclude that this modification promotes its release from less condensed and nucleolar chromatin after G2.

scholarly journals Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

2015 ◽  
Vol 112 (10) ◽  
pp. E1077-E1085 ◽  
Author(s):  
Neha Chauhan ◽  
Myriam Visram ◽  
Alvaro Cristobal-Sarramian ◽  
Florian Sarkleti ◽  
Sepp D. Kohlwein
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Sphingolipid Metabolism ◽  
Dependent Manner ◽  
Cycle Progression ◽  
Checkpoint Kinase ◽  
Cell Cycle Delay ◽  
A Cell ◽  
Morphogenesis Checkpoint ◽  
Cycle Dependent

Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle–dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle–dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated long-chain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2ACdc55) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle.

scholarly journals Fragile X–Related Protein 1 Regulates Nucleoporin Localization in a Cell Cycle–Dependent Manner

2021 ◽  
Vol 9 ◽  
Author(s):  
Arantxa Agote-Arán ◽  
Junyan Lin ◽  
Izabela Sumara
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Fragile X ◽  
Protein Translation ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Dependent Manner ◽  
Independent Manner ◽  
Cycle Dependent

Nuclear pore complexes (NPCs) are embedded in the nuclear envelope (NE) where they ensure the transport of macromolecules between the nucleus and the cytoplasm. NPCs are built from nucleoporins (Nups) through a sequential assembly order taking place at two different stages during the cell cycle of mammalian cells: at the end of mitosis and during interphase. In addition, fragile X–related proteins (FXRPs) can interact with several cytoplasmic Nups and facilitate their localization to the NE during interphase likely through a microtubule-dependent mechanism. In the absence of FXRPs or microtubule-based transport, Nups aberrantly localize to the cytoplasm forming the so-called cytoplasmic nucleoporin granules (CNGs), compromising NPCs’ function on protein export. However, it remains unknown if Nup synthesis or degradation mechanisms are linked to the FXRP–Nup pathway and if and how the action of FXRPs on Nups is coordinated with the cell cycle progression. Here, we show that Nup localization defects observed in the absence of FXR1 are independent of active protein translation. CNGs are cleared in an autophagy- and proteasome-independent manner, and their presence is restricted to the early G1 phase of the cell cycle. Our results thus suggest that a pool of cytoplasmic Nups exists that contributes to the NPC assembly specifically during early G1 to ensure NPC homeostasis at a short transition from mitosis to the onset of interphase.

scholarly journals The microtubule plus-end tracking protein Bik1 is required for chromosome congression

2021 ◽  
Author(s):  
Alexander Julner ◽  
Marjan Abbasi ◽  
Victoria Menendez Benito
Keyword(s):  
Cell Cycle ◽  
Nuclear Export ◽  
Cell Cycle Progression ◽  
Nuclear Export Signal ◽  
Microtubule Dynamics ◽  
Dependent Manner ◽  
Chromosome Congression ◽  
A Cell ◽  
Cycle Dependent ◽  
Export Signal

During mitosis, sister chromatids congress on either side of the spindle equator to facilitate the correct partitioning of the genomic material. Chromosome congression requires a finely tuned control of microtubule dynamics by the kinesin motor proteins. In Saccharomyces cerevisiae, the kinesin proteins Cin8, Kip1, and Kip3 have pivotal roles in chromosome congression. It has been hypothesized that additional proteins that modulate microtubule dynamics are also involved. Here, we show that the microtubule plus-end tracking protein Bik1 (the budding yeast ortholog of CLIP-170) is essential for chromosome congression. We find that nuclear Bik1 localizes to the kinetochores in a cell-cycle-dependent manner. Disrupting the nuclear pool of Bik1 with a nuclear export signal (Bik1-NES) leads to a slower cell cycle progression characterized by a delayed metaphase-anaphase transition. Bik1-NES cells have mispositioned kinetochores along the spindle in metaphase. Furthermore, using proximity-dependent methods, we identify Cin8 as an interaction partner of Bik1. Deleting CIN8 reduces the amount of Bik1 at the spindle. In contrast, Cin8 retains its typical bilobed distribution in Bik1-NES and does not localize to the unclustered kinetochores characteristic of Bik1-NES cells. Thus, we propose that Bik1 functions together with Cin8 to regulate kinetochore-microtubule dynamics for correct kinetochore positioning and chromosome congression.

scholarly journals Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Proliferation

2016 ◽  
Vol 36 (19) ◽  
pp. 2487-2502 ◽  
Author(s):  
Shakur Mohibi ◽  
Shashank Srivastava ◽  
Aditya Bele ◽  
Sameer Mirza ◽  
Hamid Band ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Histone Acetylation ◽  
Cell Cycle Progression ◽  
Site Directed Mutagenesis ◽  
Dependent Manner ◽  
Cycle Progression ◽  
Functional Roles ◽  
A Cell ◽  
Cycle Dependent

Alteration/deficiency in activation 3 (ADA3) is an essential component of specific histone acetyltransferase (HAT) complexes. We have previously shown that ADA3 is required for establishing global histone acetylation patterns and for normal cell cycle progression (S. Mohibi et al., J Biol Chem 287:29442–29456, 2012,http://dx.doi.org/10.1074/jbc.M112.378901). Here, we report that these functional roles of ADA3 require its acetylation. We show that ADA3 acetylation, which is dynamically regulated in a cell cycle-dependent manner, reflects a balance of coordinated actions of its associated HATs, GCN5, PCAF, and p300, and a new partner that we define, the deacetylase SIRT1. We use mass spectrometry and site-directed mutagenesis to identify major sites of ADA3 acetylated by GCN5 and p300. Acetylation-defective mutants are capable of interacting with HATs and other components of HAT complexes but are deficient in their ability to restore ADA3-dependent global or locus-specific histone acetylation marks and cell proliferation inAda3-deleted murine embryonic fibroblasts (MEFs). Given the key importance of ADA3-containing HAT complexes in the regulation of various biological processes, including the cell cycle, our study presents a novel mechanism to regulate the function of these complexes through dynamic ADA3 acetylation.

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 Visualizing the complex functions and mechanisms of the anaphase promoting complex/cyclosome (APC/C)

Open Biology ◽  
2017 ◽  
Vol 7 (11) ◽  
pp. 170204 ◽  
Author(s):  
Claudio Alfieri ◽  
Suyang Zhang ◽  
David Barford
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Dependent Manner ◽  
Cell Cycle Regulators ◽  
Anaphase Promoting Complex ◽  
Polyubiquitin Chains ◽  
A Cell ◽  
Specific Proteins ◽  
Cycle Dependent

The anaphase promoting complex or cyclosome (APC/C) is a large multi-subunit E3 ubiquitin ligase that orchestrates cell cycle progression by mediating the degradation of important cell cycle regulators. During the two decades since its discovery, much has been learnt concerning its role in recognizing and ubiquitinating specific proteins in a cell-cycle-dependent manner, the mechanisms governing substrate specificity, the catalytic process of assembling polyubiquitin chains on its target proteins, and its regulation by phosphorylation and the spindle assembly checkpoint. The past few years have witnessed significant progress in understanding the quantitative mechanisms underlying these varied APC/C functions. This review integrates the overall functions and properties of the APC/C with mechanistic insights gained from recent cryo-electron microscopy (cryo-EM) studies of reconstituted human APC/C complexes.

scholarly journals Cell cycle–dependent spatial segregation of telomerase from sites of DNA damage

2017 ◽  
Vol 216 (8) ◽  
pp. 2355-2371 ◽  
Author(s):  
Faissal Ouenzar ◽  
Maxime Lalonde ◽  
Hadrien Laprade ◽  
Geneviève Morin ◽  
Franck Gallardo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Single Molecule ◽  
De Novo ◽  
Dependent Manner ◽  
Dna Double Strand Breaks ◽  
Yeast Telomerase ◽  
A Cell ◽  
Spatial Exclusion ◽  
Cycle Dependent

Telomerase can generate a novel telomere at DNA double-strand breaks (DSBs), an event called de novo telomere addition. How this activity is suppressed remains unclear. Combining single-molecule imaging and deep sequencing, we show that the budding yeast telomerase RNA (TLC1 RNA) is spatially segregated to the nucleolus and excluded from sites of DNA repair in a cell cycle–dependent manner. Although TLC1 RNA accumulates in the nucleoplasm in G1/S, Pif1 activity promotes TLC1 RNA localization in the nucleolus in G2/M. In the presence of DSBs, TLC1 RNA remains nucleolar in most G2/M cells but accumulates in the nucleoplasm and colocalizes with DSBs in rad52Δ cells, leading to de novo telomere additions. Nucleoplasmic accumulation of TLC1 RNA depends on Cdc13 localization at DSBs and on the SUMO ligase Siz1, which is required for de novo telomere addition in rad52Δ cells. This study reveals novel roles for Pif1, Rad52, and Siz1-dependent sumoylation in the spatial exclusion of telomerase from sites of DNA repair.

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