scholarly journals Constricted migration increases DNA damage and independently represses cell cycle

2018 ◽  
Vol 29 (16) ◽  
pp. 1948-1962 ◽  
Author(s):  
Charlotte R. Pfeifer ◽  
Yuntao Xia ◽  
Kuangzheng Zhu ◽  
Dazhen Liu ◽  
Jerome Irianto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Fate ◽  
Nuclear Lamina ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Cell Cycle Reentry ◽  
Γh2ax Foci ◽  
And Migration

Cell migration through dense tissues or small capillaries can elongate the nucleus and even damage it, and any impact on cell cycle has the potential to affect various processes including carcinogenesis. Here, nuclear rupture and DNA damage increase with constricted migration in different phases of cell cycle—which we show is partially repressed. We study several cancer lines that are contact inhibited or not and that exhibit diverse frequencies of nuclear lamina rupture after migration through small pores. DNA repair factors invariably mislocalize after migration, and an excess of DNA damage is evident as pan-­nucleoplasmic foci of phosphoactivated ATM and γH2AX. Foci counts are suppressed in late cell cycle as expected of mitotic checkpoints, and migration of contact-inhibited cells through large pores into sparse microenvironments leads also as expected to cell-cycle reentry and no effect on a basal level of damage foci. Constricting pores delay such reentry while excess foci occur independent of cell-cycle phase. Knockdown of repair factors increases DNA damage independent of cell cycle, consistent with effects of constricted migration. Because such migration causes DNA damage and impedes proliferation, it illustrates a cancer cell fate choice of “go or grow.”

scholarly journals Human SKI is a telomere-associated complex involved in DNA-RNA hybrid control and telomere stability

2020 ◽  
Author(s):  
Emilia Herrera-Moyano ◽  
Rosa Maria Porreca ◽  
Lepakshi Ranjha ◽  
Roser Gonzalez-Franco ◽  
Eleni Skourti ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Mrna Decay ◽  
Hybrid Control ◽  
Replication Stress ◽  
Rna Helicase ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Telomeric Dna ◽  
Non Coding Rnas

SummarySuper killer (SKI) complex is a well-known cyplasmic 3’ to 5’ mRNA decay complex that functions with the exosome to degrade excessive and aberrant mRNAs. Recently, SKIV2L, the 3’ to 5’ RNA helicase of the human SKI (hSKI) complex was implicated in the degradation of nuclear non-coding RNAs escaping to the cytoplasm. Here, we show that hSKI is also present in the nucleus, on chromatin and in particular at telomeres during the G2 cell cycle phase. hSKI preferentially binds single stranded telomeric DNA and DNA-RNA hybrids, and SKIV2L interacts with telomeric Shelterin factors TRF1, TIN2, TPP1 and POT1. Loss of SKIV2L leads to telomere loss, DNA damage activation and fragility, which we attribute to replication stress caused by the accumulation of telomeric DNA-RNA hybrids. Our results reveal a nuclear function of the hSKI complex and implicate SKIV2L in averting DNA-RNA hybrid-dependent replication stress at human telomeres.

scholarly journals DNA damage checkpoint dynamics drive cell cycle phase transitions

2017 ◽  
Author(s):  
Hui Xiao Chao ◽  
Cere E. Poovey ◽  
Ashley A. Privette ◽  
Gavin D. Grant ◽  
Hui Yan Chao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Phase Transitions ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Dna Damage Checkpoints

ABSTRACTDNA damage checkpoints are cellular mechanisms that protect the integrity of the genome during cell cycle progression. In response to genotoxic stress, these checkpoints halt cell cycle progression until the damage is repaired, allowing cells enough time to recover from damage before resuming normal proliferation. Here, we investigate the temporal dynamics of DNA damage checkpoints in individual proliferating cells by observing cell cycle phase transitions following acute DNA damage. We find that in gap phases (G1 and G2), DNA damage triggers an abrupt halt to cell cycle progression in which the duration of arrest correlates with the severity of damage. However, cells that have already progressed beyond a proposed “commitment point” within a given cell cycle phase readily transition to the next phase, revealing a relaxation of checkpoint stringency during later stages of certain cell cycle phases. In contrast to G1 and G2, cell cycle progression in S phase is significantly less sensitive to DNA damage. Instead of exhibiting a complete halt, we find that increasing DNA damage doses leads to decreased rates of S-phase progression followed by arrest in the subsequent G2. Moreover, these phase-specific differences in DNA damage checkpoint dynamics are associated with corresponding differences in the proportions of irreversibly arrested cells. Thus, the precise timing of DNA damage determines the sensitivity, rate of cell cycle progression, and functional outcomes for damaged cells. These findings should inform our understanding of cell fate decisions after treatment with common cancer therapeutics such as genotoxins or spindle poisons, which often target cells in a specific cell cycle phase.

scholarly journals DNA damage-induced cell-cycle phase regulation of p53 and p21waf1 in normal and ATM-defective cells

Oncogene ◽  
2003 ◽  
Vol 22 (49) ◽  
pp. 7866-7869 ◽  
Author(s):  
Domenico Delia ◽  
Enrico Fontanella ◽  
Cristina Ferrario ◽  
Luciana Chessa ◽  
Shuki Mizutani
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Phase Regulation

Cell cycle phase specificity in the potentiation of etoposide-induced DNA damage and apoptosis by KN-62, an inhibitor of calcium-calmodulin-dependent enzymes

2001 ◽  
Vol 61 (1) ◽  
pp. 49-54 ◽  
Author(s):  
Masako Aoyama ◽  
Dale R Grabowski ◽  
Katherine A Holmes ◽  
Lisa A Rybicki ◽  
Ronald M Bukowski ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Calcium Calmodulin Dependent

scholarly journals Visualizing Cell Cycle Phase Organization and Control During Neural Lineage Elaboration

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2112
Author(s):  
Fatma Rabia Urun ◽  
Adrian W Moore
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Cell Types ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Cell Cycle Regulators ◽  
Neural Lineage ◽  
Fate Control ◽  
A Cell ◽  
Cell Fate Control

In neural precursors, cell cycle regulators simultaneously control both progression through the cell cycle and the probability of a cell fate switch. Precursors act in lineages, where they transition through a series of cell types, each of which has a unique molecular identity and cellular behavior. Thus, investigating links between cell cycle and cell fate control requires simultaneous identification of precursor type and cell cycle phase, as well as an ability to read out additional regulatory factor expression or activity. We use a combined FUCCI-EdU labelling protocol to do this, and then apply it to the embryonic olfactory neural lineage, in which the spatial position of a cell correlates with its precursor identity. Using this integrated model, we find the CDKi p27KIP1 has different regulation relative to cell cycle phase in neural stem cells versus intermediate precursors. In addition, Hes1, which is the principle transcriptional driver of neural stem cell self-renewal, surprisingly does not regulate p27KIP1 in this cell type. Rather, Hes1 indirectly represses p27KIP1 levels in the intermediate precursor cells downstream in the lineage. Overall, the experimental model described here enables investigation of cell cycle and cell fate control linkage from a single precursor through to a lineage systems level.

scholarly journals Ectopic restriction of DNA repair reveals that UNG2 excises AID-induced uracils predominantly or exclusively during G1 phase

2012 ◽  
Vol 209 (5) ◽  
pp. 965-974 ◽  
Author(s):  
George Sharbeen ◽  
Christine W.Y. Yee ◽  
Adrian L. Smith ◽  
Christopher J. Jolly
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Point Mutations ◽  
Affinity Maturation ◽  
Cell Cycle Phase ◽  
G1 Phase ◽  
Cycle Phase ◽  
Base Pairs ◽  
Inhibitor Peptide

Immunoglobulin (Ig) affinity maturation requires the enzyme AID, which converts cytosines (C) in Ig genes into uracils (U). This alone produces C:G to T:A transition mutations. Processing of U:G base pairs via U N-glycosylase 2 (UNG2) or MutSα generates further point mutations, predominantly at G:C or A:T base pairs, respectively, but it is unclear why processing is mutagenic. We aimed to test whether the cell cycle phase of U processing determines fidelity. Accordingly, we ectopically restricted UNG2 activity in vivo to predefined cell cycle phases by fusing a UNG2 inhibitor peptide to cell cycle–regulated degradation motifs. We found that excision of AID-induced U by UNG2 occurs predominantly during G1 phase, inducing faithful repair, mutagenic processing, and class switching. Surprisingly, UNG2 does not appear to process U:G base pairs at all in Ig genes outside G1 phase.

scholarly journals Flow cytometric analysis of the cell cycle phase specificity of DNA damage induced by radiation, hydrogen peroxide and doxorubicin

2002 ◽  
Vol 23 (3) ◽  
pp. 389-401 ◽  
Author(s):  
Alan J. Potter ◽  
Katherine A. Gollahon ◽  
Ben J.A. Palanca ◽  
Mary J. Harbert ◽  
Young M. Choi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Flow Cytometric Analysis ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Flow Cytometric
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