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Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150647 | GEO | 2021/05/11

REPOSITORIES: GEO

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Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [sWGS]

Project description:Human embryonic stem cells (hESC) and cancer cells rapidly divide with a short G1/S-phase causing increased replicative stress (RS). Since both in vitro cultured hESCs and most high-risk neuroblastomas have large chromosome 17q gains (17q+), we hypothesize that this may provide a "RS-resistance phenotype". We co-cultured parental cells and a derived hESC line with 17q+ under normal growth conditions and under RS. We could show a proliferative ad-vantage of hESC with 13q+17q+ over wild type by measurement of the cumulative growth and molecular analysis for chromosomal copy number analysis. To monitor effects of 17q+ on RS-resistance, cell cycle and transcriptome analysis were performed. In conclusion, we show that extra chromosomal aberrations, such as 17q+, provide proliferative advantage to hESC under RS and suggest that this phenomenon explains the high incidence of 17q+ in in vitro cultured hESC lines.

2021-05-11 | GSE150645 | GEO

Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [RNA-Seq]

2021-05-11 | GSE150639 | GEO

Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [targeted exome sequencing]

2021-05-11 | GSE155181 | GEO

Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment

Project description:Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment

| PRJNA633092 | ENA

Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [sWGS]

Project description:Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [sWGS]

| PRJNA633094 | ENA

Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [RNA-Seq]

Project description:Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [RNA-Seq]

| PRJNA633080 | ENA

Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [targeted exome sequencing]

Project description:Transcriptional profilling of hESC with and without 17q gain upon induction of replicative stress through HU treatment [targeted exome sequencing]

| PRJNA648929 | ENA

Wee1 is required to sustain ATR/Chk1 signaling upon replicative stress.

Project description:The therapeutic efficacy of nucleoside analogues, e.g. gemcitabine, against cancer cells can be augmented by inhibitors of checkpoint kinases, including Wee1, ATR, and Chk1. We have compared the chemosensitizing effect of these inhibitors in cells derived from pancreatic cancer, a tumor entity where gemcitabine is part of the first-line therapeutic regimens, and in osteosarcoma-derived cells. As expected, all three inhibitors rendered cancer cells more sensitive to gemcitabine, but Wee1 inhibition proved to be particularly efficient in this context. Investigating the reasons for this potent sensitizing effect, we found that Wee1 inhibition or knockdown not only blocked Wee1 activity, but also reduced the activation of ATR/Chk1 in gemcitabine-treated cells. Combination of several inhibitors revealed that Wee1 inhibition requires Cyclin-dependent kinases 1 and 2 (Cdk1/2) and Polo-like kinase 1 (Plk1) to reduce ATR/Chk1 activity. Through activation of Cdks and Plk1, Wee1 inhibition reduces Claspin and CtIP levels, explaining the impairment in ATR/Chk1 activity. Taken together, these results confer a consistent signaling pathway reaching from Wee1 inhibition to impaired Chk1 activity, mechanistically dissecting how Wee1 inhibitors not only dysregulate cell cycle progression, but also enhance replicative stress and chemosensitivity towards nucleoside analogues.

| S-EPMC4537000 | biostudies-literature

Checkpoint-dependent RNR induction promotes fork restart after replicative stress.

Project description:The checkpoint kinase Rad53 is crucial to regulate DNA replication in the presence of replicative stress. Under conditions that interfere with the progression of replication forks, Rad53 prevents Exo1-dependent fork degradation. However, although EXO1 deletion avoids fork degradation in rad53 mutants, it does not suppress their sensitivity to the ribonucleotide reductase (RNR) inhibitor hydroxyurea (HU). In this case, the inability to restart stalled forks is likely to account for the lethality of rad53 mutant cells after replication blocks. Here we show that Rad53 regulates replication restart through the checkpoint-dependent transcriptional response, and more specifically, through RNR induction. Thus, in addition to preventing fork degradation, Rad53 prevents cell death in the presence of HU by regulating RNR-expression and localization. When RNR is induced in the absence of Exo1 and RNR negative regulators, cell viability of rad53 mutants treated with HU is increased and the ability of replication forks to restart after replicative stress is restored.

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PARG is dispensable for recovery from transient replicative stress but required to prevent detrimental accumulation of poly(ADP-ribose) upon prolonged replicative stress.

Project description:Poly(ADP-ribosyl)ation is involved in numerous bio-logical processes including DNA repair, transcription and cell death. Cellular levels of poly(ADP-ribose) (PAR) are regulated by PAR polymerases (PARPs) and the degrading enzyme PAR glycohydrolase (PARG), controlling the cell fate decision between life and death in response to DNA damage. Replication stress is a source of DNA damage, leading to transient stalling of replication forks or to their collapse followed by the generation of double-strand breaks (DSB). The involvement of PARP-1 in replicative stress response has been described, whereas the consequences of a deregulated PAR catabolism are not yet well established. Here, we show that PARG-deprived cells showed an enhanced sensitivity to the replication inhibitor hydroxyurea. PARG is dispensable to recover from transient replicative stress but is necessary to avoid massive PAR production upon prolonged replicative stress, conditions leading to fork collapse and DSB. Extensive PAR accumulation impairs replication protein A association with collapsed forks resulting in compromised DSB repair via homologous recombination. Our results highlight the critical role of PARG in tightly controlling PAR levels produced upon genotoxic stress to prevent the detrimental effects of PAR over-accumulation.

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