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

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.

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Response of Thyroid Follicular Cells to Gamma Irradiation Compared to Proton Irradiation. I. Initial Characterization of DNA Damage, Micronucleus Formation, Apoptosis, Cell Survival, and Cell Cycle Phase Redistribution

Radiation Research ◽

10.1667/0033-7587(2001)155[0032:rotfct]2.0.co;2 ◽

2001 ◽

Vol 155 (1) ◽

pp. 32-42 ◽

Cited By ~ 57

Author(s):

L. M. Green ◽

D. K. Murray ◽

D. T. Tran ◽

A. M. Bant ◽

G. Kazarians ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Survival ◽

Proton Irradiation ◽

Cell Cycle Phase ◽

Cycle Phase ◽

Follicular Cells ◽

Initial Characterization ◽

Thyroid Follicular Cells

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Kinetics of the UV-induced DNA damage response in relation to cell cycle phase. Correlation with DNA replication

Cytometry Part A ◽

10.1002/cyto.a.20839 ◽

2009 ◽

pp. n/a-n/a ◽

Cited By ~ 9

Author(s):

Hong Zhao ◽

Frank Traganos ◽

Zbigniew Darzynkiewicz

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Replication ◽

Dna Damage Response ◽

Cell Cycle Phase ◽

Phase Correlation ◽

Cycle Phase ◽

Damage Response ◽

Kinetics Of

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DNA damage checkpoint dynamics drive cell cycle phase transitions

10.1101/137307 ◽

2017 ◽

Cited By ~ 1

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.

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

Oncogene ◽

10.1038/sj.onc.1207086 ◽

2003 ◽

Vol 22 (49) ◽

pp. 7866-7869 ◽

Cited By ~ 21

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

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

Biochemical Pharmacology ◽

10.1016/s0006-2952(00)00539-6 ◽

2001 ◽

Vol 61 (1) ◽

pp. 49-54 ◽

Cited By ~ 4

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

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Constricted migration increases DNA damage and independently represses cell cycle

Molecular Biology of the Cell ◽

10.1091/mbc.e18-02-0079 ◽

2018 ◽

Vol 29 (16) ◽

pp. 1948-1962 ◽

Cited By ~ 37

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.”

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