Structural Basis for DNA Damage–Dependent Poly(ADP-ribosyl)ation by Human PARP-1

Langelier, Marie-France; Planck, Jamie L.; Roy, Sudeep; Pascal, John M.

doi:10.1126/science.1216338

Cited by 546 publications

(783 citation statements)

References 47 publications

(55 reference statements)

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“…2B) combined with newly available structural data on noncatalytic domains (Langelier et al, 2008(Langelier et al, , 2011(Langelier et al, , 2012Loeffler et al, 2011;Ali et al, 2012;Hassler and Ladurner, 2012) may suggest key structural insights into the DNA-trapping activity of PARP inhibitors. The crystal structure of the "near" full-length PARP1 enzyme containing 1) zincfinger domains Zn1 and Zn3, 2) WGR domain named after a conserved Trp-Gly-Arg sequence, and 3) CAT domain consisting of HD-ARTD subdomains bound to a DNA DSB (PDB ID: 4DQY) demonstrates that DNA binding by Zn1, Zn3, and WGR domains destabilizes the CAT domain, thereby activating the PARP enzymatic activity (Langelier et al, 2012). Specifically, structural changes upon DNA binding in the noncatalytic domains lead to displacements of Leu698 and Leu701 residues from the hydrophobic core of the HD (Fig.…”

Section: Structural Basis For Parp-dna Trappingmentioning

confidence: 99%

Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

181

188

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Recent findings indicate that a major mechanism by which poly (ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for singleagent and combination treatments.

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Section: Structural Basis For Parp-dna Trappingmentioning

confidence: 99%

Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

181

188

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“…A third ZF domain (ZF3), which has recently been characterized, is distinct in structure and function from ZF1 and ZF2 (23). To identify the domains of PARP1 that interact with TREX1, we generated a V5-tagged full-length PARP1 and a panel of deletion mutants ( Fig.…”

Section: Identification Of Parp1 As a Novel Proteinmentioning

confidence: 99%

The 3′–5′ DNA Exonuclease TREX1 Directly Interacts with Poly(ADP-ribose) Polymerase-1 (PARP1) during the DNA Damage Response

Miyazaki

Kim

Yoon

et al. 2014

Journal of Biological Chemistry

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Background: TREX1 is a 3Ј-5Ј DNA exonuclease, and mutations in human TREX1 are associated with autoimmune/ inflammatory diseases. Results: TREX1 interacts with poly(ADP-ribose) polymerase-1 (PARP1). Conclusion: TREX1 contributes to maintenance of suitable PARP1 levels and its functions in the DNA damage response. Significance: Identification of the molecular mechanism of TREX1 is necessary for understanding the development or progression of TREX1-associated diseases.

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“…Upon DNA damage, PARP1 is recruited to single-strand breaks (SSB), where it becomes activated (10) and catalyzes the poly(ADP-ribosyl)ation of local substrates, including histones. As poly(ADP-ribosyl)ation advances and PAR polymers extend, histones progressively acquire negative charges, causing their electrostatic repulsion from interacting proteins and DNA (11).…”

Section: Introductionmentioning

confidence: 99%

Cisplatin Resistance Associated with PARP Hyperactivation

et al. 2013

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Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR high ) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7);

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Structural Basis for DNA Damage–Dependent Poly(ADP-ribosyl)ation by Human PARP-1

Cited by 546 publications

References 47 publications

Trapping Poly(ADP-Ribose) Polymerase

Trapping Poly(ADP-Ribose) Polymerase

The 3′–5′ DNA Exonuclease TREX1 Directly Interacts with Poly(ADP-ribose) Polymerase-1 (PARP1) during the DNA Damage Response

Cisplatin Resistance Associated with PARP Hyperactivation

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