Targeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer

Steffen, Jamin D.; Tholey, Renee; Langelier, Marie-France; Planck, Jamie L.; Schiewer, Matthew J.; Lal, Shruti; Bildzukewicz, Nikolai A.; Yeo, Charles J.; Knudsen, Karen E.; Brody, Jonathan R.; Pascal, John M.

doi:10.1158/0008-5472.can-13-1701

Cited by 55 publications

(62 citation statements)

References 28 publications

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“…Third, is it possible to specifically target the transcriptional regulatory function of PARP-1 in cancer therapy? Recent evidence suggests that specific modules of PARP-1 regulate allosteric communication, and abrogation of this communication supports the contention of context-dependent transcriptional regulation by PARP-1, but not the DDR function of PARP-1 (93). Given these compelling findings, pursuit towards more specifically targeting PARP-1 transcriptional regulation is currently underway.…”

Section: Discussionmentioning

confidence: 67%

Transcriptional Roles of PARP1 in Cancer

Schiewer

Knudsen

2014

Molecular Cancer Research

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159

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Poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant, ubiquitously expressed NAD+-dependent nuclear enzyme that has prognostic value for a multitude of human cancers. PARP-1 activity serves to poly (ADP-ribose)-ylate the vast majority of known client proteins and affects a number of cellular and biological outcomes, by mediating DNA damage response (DDR), base-excision repair (BER), and DNA strand break (DSB) pathways. PARP-1 is also critically important for the maintenance of genomic integrity, as well as chromatin dynamics and transcriptional regulation. Evidence also indicates that PARP-directed therapeutics are “synthetic lethal” in BRCA1/2-dieficient model systems. Strikingly, recent studies have unearthed exciting new transcriptional-regulatory roles for PARP-1, which has profound implications for human malignancies and will be reviewed herein.

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Section: Discussionmentioning

confidence: 67%

Transcriptional Roles of PARP1 in Cancer

Schiewer

Knudsen

2014

Molecular Cancer Research

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159

136

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“…Historically, most PARPis are nicotinamide mimics that target the PARP NAD + -binding pocket (Steffen et al 2013), making them broadly effective against many PARPs. The genetic disruption of PARP-1 interdomain contacts prevents DNA damage-dependent catalytic activation and shows increased sensitivity to platinum-based anti-cancer agents while having no effect on PARP-1 recruitment to sites of DNA damage or transcriptional regulation (Steffen et al 2014). These results highlight the potential of synergistic drug combinations using allosteric PARPis with DNA-damaging agents.…”

Section: Molecular Strategies For Targeting Parpsmentioning

confidence: 92%

“…A recent study explored a new strategy that targets allosteric regulation as a selective way of inhibiting PARP-1 (Steffen et al 2014). Historically, most PARPis are nicotinamide mimics that target the PARP NAD + -binding pocket (Steffen et al 2013), making them broadly effective against many PARPs.…”

Section: Molecular Strategies For Targeting Parpsmentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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“…The Flag and Flag-EBNA1 vectors were kind gifts from Paul M. Lieberman (The Wistar Institute, Philadelphia, PA). The full-length cDNA plasmid constructs encoding human PARP1 WT and catalytically inactive PARP1 (E998A) were provided by John Pascal (Jefferson University, Philadelphia, PA) and described previously (22,23).…”

Section: Methodsmentioning

confidence: 99%

Epstein-Barr Virus Oncoprotein LMP1 Mediates Epigenetic Changes in Host Gene Expression through PARP1

Martin

Lupey

Tempera

2016

J Virol

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The latent infection of Epstein-Barr virus (EBV) is associated with 1% of human cancer incidence. Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) that mediate EBV replication during latency. In this study, we detail the mechanisms that drive cellular PARylation during latent EBV infection and the effects of PARylation on host gene expression and cellular function. EBV-infected B cells had higher PAR levels than EBV-negative B cells. Moreover, cellular PAR levels were up to 2-fold greater in type III than type I latently infected EBV B cells. We identified a positive association between expression of the EBV genome-encoded latency membrane protein 1 (LMP1) and PAR levels that was dependent upon PARP1. PARP1 regulates gene expression by numerous mechanisms, including modifying chromatin structure and altering the function of chromatin-modifying enzymes. Since LMP1 is essential in establishing EBV latency and promoting tumorigenesis, we explored the model that disruption in cellular PARylation, driven by LMP1 expression, subsequently promotes epigenetic alterations to elicit changes in host gene expression. PARP1 inhibition resulted in the accumulation of the repressive histone mark H3K27me3 at a subset of LMP1-regulated genes. Inhibition of PARP1, or abrogation of PARP1 expression, also suppressed the expression of LMP1-activated genes and LMP1-mediated cellular transformation, demonstrating an essential role for PARP1 activity in LMP1-induced gene expression and cellular transformation associated with LMP1. In summary, we identified a novel mechanism by which LMP1 drives expression of host tumor-promoting genes by blocking generation of the inhibitory histone modification H3K27me3 through PARP1 activation. IMPORTANCEEBV is causally linked to several malignancies and is responsible for 1% of cancer incidence worldwide. The EBV-encoded protein LMP1 is essential for promoting viral tumorigenesis by aberrant activation of several well-known intracellular signaling pathways. We have identified and defined an additional novel molecular mechanism by which LMP1 regulates the expression of tumor-promoting host genes. We found that LMP1 activates the cellular protein PARP1, leading to a decrease in a repressive histone modification, accompanied by induction in expression of multiple cancer-related genes. PARP1 inhibition or depletion led to a decrease in LMP1-induced cellular transformation. Therefore, targeting PARP1 activity may be an effective treatment for EBV-associated malignancies. The Epstein-Barr virus (EBV) is a human gammaherpesvirus that latently infects approximately 95% of the population worldwide (1). Latent EBV infection contributes to 1% of human cancers, including Burkitt's lymphoma and nasopharyngeal carcinoma (2, 3). To establish a latent infection in a naive B cell, EBV first adopts a type III latent gene expression program in which all latency genes are expressed to provide intracellular signals to the infected B cell th...

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Targeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer

Cited by 55 publications

References 28 publications

Transcriptional Roles of PARP1 in Cancer

Transcriptional Roles of PARP1 in Cancer

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

Epstein-Barr Virus Oncoprotein LMP1 Mediates Epigenetic Changes in Host Gene Expression through PARP1

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