Poly(ADP-ribose) Polymerase Activity Prevents Signaling Pathways for Cell Cycle Arrest after DNA Methylating Agent Exposure

Mouse fibroblasts, deficient in DNA polymerase β, are hypersensitive to monofunctional DNA methylating agents such as methyl methanesulfonate (MMS). Both wild-type and, in particular, repair-deficient DNA polymerase β null cells are highly sensitized to the cytotoxic effects of MMS by 4-amino-1,8-naphthalimide (4-AN), an inhibitor of poly(ADP-ribose) polymerase (PARP) activity. Experiments with synchronized cells suggest that exposure during S-phase of the cell cycle is required for the 4-AN effect. 4-AN elicits a similar extreme sensitization to the thymidine analog, 5-hydroxymethyl-2′-deoxyuridine, implicating the requirement for an intermediate of DNA repair. In PARP-1-expressing fibroblasts treated with a combination of MMS and 4-AN, a complete inhibition of DNA synthesis is apparent after 4 h, and by 24 h, all cells are arrested in S-phase of the cell cycle. Continuous incubation with 4-AN is required to maintain the cell cycle arrest. Caffeine, an inhibitor of the upstream checkpoint kinases ATM (ataxia telangiectasia-mutated) and ATR (ATM and Rad3-related), has no effect on the early inhibition of DNA synthesis, but cells are no longer able to maintain the block after 8 h. Instead, the addition of caffeine leads to arrest of cells in G2/M rather than S-phase after 24 h. Analysis of signaling pathways in cell extracts reveals an activation of Chk1 after treatment with MMS and 4-AN, which can be suppressed by caffeine. Our results suggest that inhibition of PARP activity results in sensitization to MMS through maintenance of an ATR and Chk1-dependent S-phase checkpoint.

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Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers

Oncogene ◽

10.1038/s41388-021-01710-y ◽

2021 ◽

Author(s):

Reem Ali ◽

Adel Alblihy ◽

Islam M. Miligy ◽

Muslim L. Alabdullah ◽

Mansour Alsaleem ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Dna Polymerase ◽

Synthetic Lethality ◽

Ovarian Cancer Cells ◽

Dna Polymerase Β ◽

Mesenchymal Transition ◽

Platinum Sensitivity ◽

Cycle Arrest ◽

Ovarian Cancers

AbstractTargeting PARP1 [Poly(ADP-Ribose) Polymerase 1] for synthetic lethality is a new strategy for BRCA germ-line mutated or platinum sensitive ovarian cancers. However, not all patients respond due to intrinsic or acquired resistance to PARP1 inhibitor. Development of alternative synthetic lethality approaches is a high priority. DNA polymerase β (Polβ), a critical player in base excision repair (BER), interacts with PARP1 during DNA repair. Here we show that polβ deficiency is a predictor of platinum sensitivity in human ovarian tumours. Polβ depletion not only increased platinum sensitivity but also reduced invasion, migration and impaired EMT (epithelial to mesenchymal transition) of ovarian cancer cells. Polβ small molecular inhibitors (Pamoic acid and NSC666719) were selectively toxic to BRCA2 deficient cells and associated with double-strand breaks (DSB) accumulation, cell cycle arrest and increased apoptosis. Interestingly, PARG [Poly(ADP-Ribose) Glycohydrolase] inhibitor (PDD00017273) [but not PARP1 inhibitor (Olaparib)] was synthetically lethal in polβ deficient cells. Selective toxicity to PDD00017273 was associated with poly (ADP-ribose) accumulation, reduced nicotinamide adenine dinucleotide (NAD+) level, DSB accumulation, cell cycle arrest and increased apoptosis. In human tumours, polβ-PARG co-expression adversely impacted survival in patients. Our data provide evidence that polβ targeting is a novel strategy and warrants further pharmaceutical development in epithelial ovarian cancers.

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MyoD induced cell cycle arrest is associated with increased nuclear affinity of the Rb protein.

Molecular Biology of the Cell ◽

10.1091/mbc.4.7.705 ◽

1993 ◽

Vol 4 (7) ◽

pp. 705-713 ◽

Cited By ~ 27

Author(s):

A M Thorburn ◽

P A Walton ◽

J R Feramisco

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Dna Synthesis ◽

Cell Cycle Arrest ◽

S Phase ◽

Tumor Suppressor Protein ◽

G1 Phase ◽

Induced Expression ◽

Rb Protein ◽

Cycle Arrest

In studying the mechanism through which the myogenic determination protein MyoD prevents entry into the S phase of the cell cycle, we have found a relationship between MyoD and the retinoblastoma (Rb) tumor suppressor protein. By direct needle microinjection of purified recombinant MyoD protein into quiescent fibroblasts, which were then induced to proliferate by serum, we found that MyoD arrested progression of the cell cycle, in agreement with studies utilizing expression constructs for MyoD. By studying temporal changes in cells injected with MyoD protein, it was found that MyoD did not prevent serum induced expression of the protooncogene c-Fos, an event that occurs in the G0 to G1 transition of the cycle. Injection of the MyoD protein as late as 8 h after the addition of serum still caused an inhibition in DNA synthesis, suggesting that MyoD inhibits the G1 to S transition as opposed to the G0 to G1 transition. MyoD injection did not prevent the expression of cyclin A. However MyoD injection did result in a block in the increase in Rb extractibility normally seen in late G1 phase cells. As this phenomenon is associated with the hyperphosphorylation of Rb at this point in the cell cycle and is correlated with progression into S phase, this provides further evidence that MyoD blocks the cycle late in G1.

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GTP Induces S-phase Cell-cycle Arrest and Inhibits DNA Synthesis in K562 Cells But Not in Normal Human Peripheral Lymphocytes

BMB Reports ◽

10.5483/bmbrep.2006.39.5.492 ◽

2006 ◽

Vol 39 (5) ◽

pp. 492-501 ◽

Cited By ~ 12

Author(s):

Mohammad Amin Moosavi ◽

Razieh Yazdanparast ◽

Abbas Lotfi

Keyword(s):

Cell Cycle ◽

Dna Synthesis ◽

Cell Cycle Arrest ◽

K562 Cells ◽

S Phase ◽

Phase Cell ◽

Peripheral Lymphocytes ◽

Cycle Arrest ◽

Human Peripheral Lymphocytes ◽

Normal Human

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Signaling pathways involved in cell cycle arrest during the DNA breaks

DNA Repair ◽

10.1016/j.dnarep.2021.103047 ◽

2021 ◽

Vol 98 ◽

pp. 103047

Author(s):

Fatemeh Sadoughi ◽

Jamal Hallajzadeh ◽

Zatollah Asemi ◽

Mohammad Ali Mansournia ◽

Forough Alemi ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathways ◽

Dna Breaks ◽

Cycle Arrest

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Involvement of the p38 MAPK signaling pathway in S-phase cell-cycle arrest induced by Furazolidone in human hepatoma G2 cells

Journal of Applied Toxicology ◽

10.1002/jat.2829 ◽

2012 ◽

Vol 33 (12) ◽

pp. 1500-1505 ◽

Cited By ~ 6

Author(s):

Yu Sun ◽

Shusheng Tang ◽

Xi Jin ◽

Chaoming Zhang ◽

Wenxia Zhao ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

S Phase ◽

Mapk Signaling Pathway ◽

Phase Cell ◽

Human Hepatoma ◽

Cycle Arrest

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High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1.

Molecular and Cellular Biology ◽

10.1128/mcb.17.9.5588 ◽

1997 ◽

Vol 17 (9) ◽

pp. 5588-5597 ◽

Cited By ~ 323

Author(s):

A Sewing ◽

B Wiseman ◽

A C Lloyd ◽

H Land

Keyword(s):

Cell Cycle ◽

Dna Synthesis ◽

Cell Cycle Arrest ◽

Expression Patterns ◽

Cellular Responses ◽

Specific Cell ◽

Cyclin D ◽

Inhibition Of Proliferation ◽

Cycle Arrest ◽

Signal Specificity

Activated Raf has been linked to such opposing cellular responses as the induction of DNA synthesis and the inhibition of proliferation. However, it remains unclear how such a switch in signal specificity is regulated. We have addressed this question with a regulatable Raf-androgen receptor fusion protein in murine fibroblasts. We show that Raf can cause a G1-specific cell cycle arrest through induction of p21Cip1. This in turn leads to inhibition of cyclin D- and cyclin E-dependent kinases and an accumulation of hypophosphorylated Rb. Importantly, this behavior can be observed only in response to a strong Raf signal. In contrast, moderate Raf activity induces DNA synthesis and is sufficient to induce cyclin D expression. Therefore, Raf signal specificity can be determined by modulation of signal strength presumably through the induction of distinct protein expression patterns. Similar to induction of Raf, a strong induction of activated Ras via a tetracycline-dependent promoter also causes inhibition of proliferation and p21Cip1 induction at high expression levels. Thus, p21Cip1 plays a key role in determining cellular responses to Ras and Raf signalling. As predicted by this finding we show that Ras and loss of p21 cooperate to confer a proliferative advantage to mouse embryo fibroblasts.

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Synthesis, crystal structure, cytotoxicity and action mechanism of Zn(ii) and Mn(ii) complexes with 4-([2,2′:6′,2′′-terpyridin]-4′-yl)-N,N-diethylaniline as a ligand

MedChemComm ◽

10.1039/c6md00098c ◽

2016 ◽

Vol 7 (6) ◽

pp. 1132-1137 ◽

Cited By ~ 5

Author(s):

Hua-Hong Zou ◽

Jun-Guang Wei ◽

Xiao-Huan Qin ◽

Shun-Gui Mo ◽

Qi-Pin Qin ◽

...

Keyword(s):

Crystal Structure ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

S Phase ◽

Action Mechanism ◽

Cycle Arrest ◽

G4 Dna

Two metallo-complexes inhibited telomerase by interacting with c-myc G4-DNA and induced cell cycle arrest at the S phase.

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Inhibition of Cdk2 Activation by Selected Tyrphostins Causes Cell Cycle Arrest at Late G1 and S Phase

Experimental Cell Research ◽

10.1006/excr.1998.4061 ◽

1998 ◽

Vol 241 (2) ◽

pp. 340-351 ◽

Cited By ~ 31

Author(s):

Nurit Kleinberger-Doron ◽

Noa Shelah ◽

Ricardo Capone ◽

Aviv Gazit ◽

Alexander Levitzki

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

S Phase ◽

Cycle Arrest

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Glioblastoma Multiforme Stem Cell Cycle Arrest by Alkylaminophenol through the Modulation of EGFR and CSC Signaling Pathways

Cells ◽

10.3390/cells9030681 ◽

2020 ◽

Vol 9 (3) ◽

pp. 681 ◽

Cited By ~ 3

Author(s):

Phuong Doan ◽

Aliyu Musa ◽

Akshaya Murugesan ◽

Vili Sipilä ◽

Nuno R. Candeias ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cell ◽

Glioblastoma Multiforme ◽

Cell Cycle Arrest ◽

Signaling Pathways ◽

Cell Lines ◽

Cell Population ◽

Significant Role ◽

Dependent Manner ◽

Cycle Arrest

Cancer stem cells (CSCs), a small subpopulation of cells existing in the tumor microenvironment promoting cell proliferation and growth. Targeting the stemness of the CSC population would offer a vital therapeutic opportunity. 3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), a small synthetic phenol compound, is proposed to play a significant role in controlling the CSC proliferation and survival. We assessed the potential therapeutic effects of THTMP on glioblastoma multiforme (GBM) and its underlying mechanism in various signaling pathways. To fully comprehend the effect of THTMP on the CSCs, CD133+ GBM stem cell (GSC) and CD133- GBM Non-stem cancer cells (NSCC) population from LN229 and SNB19 cell lines was used. Cell cycle arrest, apoptosis assay and transcriptome analysis were performed for individual cell population. THTMP strongly inhibited NSCC and in a subtle way for GSC in a time-dependent manner and inhibit the resistance variants better than that of temozolomide (TMZ). THTMP arrest the CSC cell population at both G1/S and G2/M phase and induce ROS-mediated apoptosis. Gene expression profiling characterize THTMP as an inhibitor of the p53 signaling pathway causing DNA damage and cell cycle arrest in CSC population. We show that the THTMP majorly affects the EGFR and CSC signaling pathways. Specifically, modulation of key genes involved in Wnt, Notch and Hedgehog, revealed the significant role of THTMP in disrupting the CSCs’ stemness and functions. Moreover, THTMP inhibited cell growth, proliferation and metastasis of multiple mesenchymal patient-tissue derived GBM-cell lines. THTMP arrests GBM stem cell cycle through the modulation of EGFR and CSC signaling pathways.

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