Cell cycle perturbations following DNA damage in the presence of ADP-ribosylation inhibitors

Jacobson, Elaine L.; Meadows, Renee Y.; Measel, John W.

doi:10.1093/carcin/6.5.711

Cited by 45 publications

(12 citation statements)

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“…PARP-1 is a nuclear enzyme that uses NAD+ as a substrate to catalyze the covalent attachment of ADP-ribose units on nuclear acceptor proteins or on PARP-1 itself 30 . In response to stress signals, PARP-1 is activated and plays key roles in DNA repair 31–33 , apoptosis 34, 35 , chromatin modulation and transcription 36, 37 and cell cycle regulation 38–41 . Many reports demonstrate that PARP-1 inhibition by genetic deletion or chemical inhibitors decreases angiogenesis during melanoma tumor growth, a transplanted lung cancer model or other pathological conditions 42–45 .…”

Section: Resultsmentioning

confidence: 99%

LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation

Mao

Lockyer

Townley-Tilson

et al. 2016

ATVB

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Objective We recently demonstrated that low-density lipoprotein receptor related protein 1 (LRP1) is required for cardiovascular development in zebrafish. However, what role LRP1 plays in angiogenesis remains to be determined. To better understand the role of LRP1 in endothelial cell function, we investigated how LRP1 regulates mouse retinal angiogenesis. Approach and results Depletion of LRP1 in endothelial cells results in increased retinal neovascularization in a mouse model of oxygen-induced retinopathy. Specifically, retinas in mice lacking endothelial LRP1 have more branching points and angiogenic sprouts at the leading edge of the newly formed vasculature. Increased endothelial proliferation as detected by Ki67 staining was observed in LRP1 deleted retinal endothelium in response to hypoxia. Using an array of biochemical and cell biology approaches, we demonstrate that poly(ADP-ribose) polymerase-1 (PARP-1) directly interacts with LRP1 in human retinal microvascular endothelial cells (HRECs). This interaction between LRP1 and PARP-1 decreases under hypoxic condition. Moreover, LRP1 knockdown results in increased PARP-1 activity and subsequent phosphorylation of both retinoblastoma protein (Rb) and cyclin-dependent kinase 2 (CDK2), which function to promote cell cycle progression and angiogenesis. Conclusions Together, these data reveal a pivotal role for LRP1 in endothelial cell proliferation and retinal neovascularization induced by hypoxia. In addition, we demonstrate for the first time the interaction between LRP1 and PARP-1 and the LRP1-dependent regulation of PARP-1 signaling pathways. These data bring forth the possibility of novel therapeutic approaches for pathological angiogenesis.

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Section: Resultsmentioning

confidence: 99%

LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation

Mao

Lockyer

Townley-Tilson

et al. 2016

ATVB

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“…In contrast, the three PARP-DBD-expressing cell lines exhibited an -2-fold increase in the fraction of cells in G2 + M after MNNG treatment. The p53-mediated G1 arrest is absent in HeLa cells (23); however, previous studies have shown that p53-positive cell lines simultaneously exposed to 3-aminobenzamide, a potent PARP inhibitor, and to alkylating agents exhibit an accumulation in G2 + M phase but not in G1 (24,25). Taken together, these results indicate that after exposure to low levels of alkylating agents, inhibition of PARP, either by 3-aminobenzamide or by production of its DBD, results in a delay in G2 + M, independent of p53 function, strongly suggesting that PARP is critical for passing through the G2 checkpoint.…”

Section: Resultsmentioning

confidence: 99%

A dominant-negative mutant of human poly(ADP-ribose) polymerase affects cell recovery, apoptosis, and sister chromatid exchange following DNA damage.

Schreiber

Hunting

Trucco

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

190

122

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leading to the trans-dominant inhibition of resident PARP activity. As a control, a cell line was constructed, producing a point-mutated version ofthe DBD, which has no affinity for DNA in vitro. Expression of the PARP-DBD had only a slight effect on undamaged cells but had drastic consequences for cells treated with genotoxic agents. Exposure of cell lines expressing the wild-type (wt) or the mutated PARP-DBD, with low doses of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) resulted in an increase in their doubling time, a G2 + M accumulation, and a marked reduction in cell survival. However, UVC irradiation had no preferential effect on the cell growth or viability of cell lines expressing the PARP-DBD. These PARP-DBD-expressing cells treated with MNNG presented the characteristic nucleosomal DNA ladder, one of the hallmarks of cell death by apoptosis. Moreover, these cells exhibited chromosomal instability as demonstrated by higher frequencies of both spontaneous and MNNG-induced sister chromatid exchanges. Surprisingly, the line producing the mutated DBD had the same behavior as those producing the wt DBD, indicating that the mechanism of action of the dominant-negative mutant involves more than its DNAbinding function. Altogether, these results strongly suggest that PARP is an element of the G2 checkpoint in mammalian cells.

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“…Furthermore, multiple reports show that PARP inhibitors increase the cytotoxicity of DNA-damaging agents and IR (19 -21). This is manifested by a delay in the progression through the S phase and accumulation of cells in G 2 /M (22,23). Although viable, both PARP-1 and PARP-2 knock-out mice display an acute sensitivity to IR and alkylating agents (24,25).…”

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confidence: 99%

Ataxia Telangiectasia Mutated (ATM) Signaling Network Is Modulated by a Novel Poly(ADP-ribose)-dependent Pathway in the Early Response to DNA-damaging Agents

Haince

Kozlov

Dawson

et al. 2007

Journal of Biological Chemistry

235

184

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Poly(ADP-ribosyl)ation is a post-translational modification that is instantly stimulated by DNA strand breaks creating a unique signal for the modulation of protein functions in DNA repair and cell cycle checkpoint pathways. Here we report that lack of poly(ADP-ribose) synthesis leads to a compromised response to DNA damage. Deficiency in poly(ADP-ribosyl)ation metabolism induces profound cellular sensitivity to DNA-damaging agents, particularly in cells deficient for the protein kinase ataxia telangiectasia mutated (ATM). At the biochemical level, we examined the significance of poly(ADP-ribose) synthesis on the regulation of early DNA damage-induced signaling cascade initiated by ATM. Using potent PARP inhibitors and PARP-1 knock-out cells, we demonstrate a functional interplay between ATM and poly(ADP-ribose) that is important for the phosphorylation of p53, SMC1, and H2AX. For the first time, we demonstrate a functional and physical interaction between the major DSB signaling kinase, ATM and poly(ADP-ribosyl)ation by PARP-1, a key enzyme of chromatin remodeling. This study suggests that poly(ADP-ribose) might serve as a DNA damage sensory molecule that is critical for early DNA damage signaling. Double-strand breaks (DSB)5 are potentially the most cytotoxic form of DNA damage in human cells because they lead to genomic rearrangements, cancer predisposition, and perhaps cell death if unrepaired or repaired incorrectly (1). Consequently, the DNA damage response involves parallel modulation of redundant signaling pathways leading to lesion detection, processing, and repair. Ataxia telangiectasia mutated (ATM) is a DNA damage-responding kinase that is rapidly activated after the induction of DSB (2). Within minutes of DNA damage induction, ATM is recruited and activated in the vicinity of DSBs, where it induces the phosphorylation of a number of proteins required for DNA damage response and repair, including proteins of MRN (Mre11/Rad50/NBS1) complex, p53, SMC1 and histone variant H2AX (3). However, the detailed mechanisms of how ATM is activated and regulates its downstream effectors are not fully understood. Although ATM activation is mainly associated with DSB formation as part of the damage detection mechanism following ionizing radiation (IR), several studies indicate that the signaling kinase ATM is also activated in response to the environmental carcinogen N-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG) (4 -6).Poly(ADP-ribose) polymerases (PARPs) are also constitutive factors of the DNA damage surveillance network, acting through a DNA break sensor function (7). Several observations indicate that poly(ADP-ribosyl)ation also plays an early role in DSB signaling and repair pathways (8 -11). PARP-1 and PARP-2 are highly activated upon binding to DNA strand interruptions and synthesize, within seconds, large amounts of the negatively charged polymer of ADP-ribose (PAR) on several nuclear proteins including themselves, histones, topoisomerase I, and DNA-dependent protein kinase (DNA-PK) (12). The immediate activat...

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Cell cycle perturbations following DNA damage in the presence of ADP-ribosylation inhibitors

Cited by 45 publications

References 0 publications

LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation

LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation

A dominant-negative mutant of human poly(ADP-ribose) polymerase affects cell recovery, apoptosis, and sister chromatid exchange following DNA damage.

Ataxia Telangiectasia Mutated (ATM) Signaling Network Is Modulated by a Novel Poly(ADP-ribose)-dependent Pathway in the Early Response to DNA-damaging Agents

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