Poly ADP-ribosylation: A DNA break signal mechanism

Althaus, Felix R.; Kleczkowska, Hanna E.; Malanga, Maria; Müntener, Cedric R; Pleschke, Jutta M.; Ebner, Maria; Auer, Bernhard

doi:10.1007/978-1-4419-8740-2_1

Cited by 52 publications

(38 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PARP-2, a closely related protein, has also been implicated in this pathway (25). PARP-1 and PARP-2 have been proposed to act as both DNA damage sensors and signal transducers to downstream effectors of cell cycle arrest and DNA repair (26). After binding damaged DNA with its zinc finger binding motif, activated PARP-1 uses NAD + as a substrate to catalyze its automodification, as well as modification of other nuclear proteins by adding ADP-ribose polymers (27).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Poly(ADP-Ribose) Polymerase Enhances Cell Death and Improves Tumor Growth Delay in Irradiated Lung Cancer Models

Albert

Cao

Kim

et al. 2007

Clinical Cancer Research

248

150

View full text Add to dashboard Cite

Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1inhibition may sensitize tumor cells to radiation. Experimental Design: We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1inhibition on irradiated tumors and tumor vasculature. Results: ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone g-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated doses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase^mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis. Conclusions: We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of Poly(ADP-Ribose) Polymerase Enhances Cell Death and Improves Tumor Growth Delay in Irradiated Lung Cancer Models

Albert

Cao

Kim

et al. 2007

Clinical Cancer Research

248

150

View full text Add to dashboard Cite

show abstract

“…PARP-1 and PARP-2 play a dual role as DNA damage sensors and signal transducers to downstream endpoints such as DNA repair and cell death pathways [3][4][5][6][7]. PARP-1 and PARP-2 bind rapidly to DNA strand breaks, become activated, and covalently modify themselves as well as other nuclear proteins.…”

Section: Introductionmentioning

confidence: 99%

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Cohausz

Blenn

Malanga

et al. 2008

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Abstract. Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor (AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG), the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2 and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved.

show abstract

“…In several pathologic situations that involve massive DNA damage, excessive activation of PARP-1 depletes cellular reserve of NAD and its precursor ATP, leading to cell death via energy failure (24,25). It recently has been shown that ROS-mediated DNA damage triggers activation of the PARP-1 and subsequent cell death (26,27). Although PARP-1-mediated cell death is thought to be necrotic (28,29), recent reports have shown that PARP-1-mediated cell death also has many features in common with apoptotic forms of the cell death (27,30).…”

Section: Introductionmentioning

confidence: 99%

Caspase-Independent Cell Death by Arsenic Trioxide in Human Cervical Cancer Cells

et al. 2004

View full text Add to dashboard Cite

Although mechanisms of arsenic trioxide (As 2 O 3 )-induced cell death have been studied extensively in hematologic cancers, those in solid cancers have yet to be clearly defined. In this study, we showed that the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus is required for As 2 O 3 -induced cell death in human cervical cancer cells. We also showed that reactive oxygen species (

show abstract

Poly ADP-ribosylation: A DNA break signal mechanism

Cited by 52 publications

References 25 publications

Inhibition of Poly(ADP-Ribose) Polymerase Enhances Cell Death and Improves Tumor Growth Delay in Irradiated Lung Cancer Models

Inhibition of Poly(ADP-Ribose) Polymerase Enhances Cell Death and Improves Tumor Growth Delay in Irradiated Lung Cancer Models

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Caspase-Independent Cell Death by Arsenic Trioxide in Human Cervical Cancer Cells

Contact Info

Product

Resources

About