Poly(ADP-ribose) polymerase inhibits DNA synthesis initiation in the absence of NAD+

Yamanaka, Hisashi; Carson, Dennis A.

doi:10.1016/0006-291x(89)92336-x

Cited by 11 publications

(5 citation statements)

References 26 publications

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“…Although one could theoretically target PARP1 by depleting its substrate NAD + or by using catalytic inhibitors10,76, the latter approach has been much more extensively explored. Initial studies performed with 3-aminobenzamide, an agent that is neither selective enough nor potent enough by current standards, demonstrated enhanced radiation sensitivity when poly(ADP-ribosyl)ation was inhibited, fuelling a structure-based search for more potent competitive inhibitors (reviewed in REF.…”

Section: How To Best Target Parps For Therapy?mentioning

confidence: 99%

PARP inhibition: PARP1 and beyond

et al. 2010

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Recent findings have thrust poly(ADP-ribose) polymerases (PARPs) into the limelight as potential chemotherapeutic targets. To provide a framework for understanding these recent observations, we review what is known about the structures and functions of the family of PARP enzymes, and then outline a series of questions that should be addressed to guide the rational development of PARP inhibitors as anticancer agents.Current efforts to develop poly(ADP-ribose) polymerase (PARP) inhibitors as anticancer drugs represent the culmination of over 40 years of research. After Paul Mandel's research group first described a nuclear enzymatic activity that synthesizes an adenine-containing RNA-like polymer 1 , independent studies by French and Japanese teams demonstrated that this polymer, designated poly(ADP-ribose) (pADPr), is composed of two ribose moieties and two phosphates per unit polymer [2][3][4][5] . The purification of an enzyme that could generate large amounts of pADPr, PARP1 (REFS 6,7 ), led to the discovery that PARP1 is activated by DNA strand breaks [8][9][10] . Seminal work by Sydney Shall's group showed that PARP1 is involved in DNA repair and also suggested the potential use of PARP inhibitors to enhance the cytotoxic effects Correspondence to G.G.P. guy.poirier@crchul.ulaval.ca. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of alkylating agents 10 . Examination of knockout mouse models 11 strengthened the hypothesis that PARP1 participates in DNA repair and simultaneously provided the first evidence for the existence of PARP2 (REF. 12 ). A parallel set of experiments demonstrated that PARP1 hyperactivation leads to nicotinamide adenine dinucleotide (NAD + ) and ATP depletion after various types of DNA damage 13,14 (BOX 1), potentially contributing to a unique form of metabolic cell death, which is now termed parthanatos 15 . PARP was thrust into the limelight by the discovery that PARP inhibition is particularly toxic in cancer cell lines 16,17 and human tumours 18 that lack BRCA1 or BRCA2. Despite this progress, there is still much that we do not understand about the biology of the PARP family and pADPr, as detailed below. Box 1 PARP1 hyperactivation and cell deathNicotinamide adenine dinucleotide (NAD + ) is the source of ADP-ribose used by poly(ADPribose) polymerases (PARPs) to produce poly(ADP-ribose) (pADPr). Because hyperactivation of PARP1 consumes the cytosolic and nuclear pools of NAD + to generate pADPr, pADPr synthesis translates DNA damage intensity into changes in cellular energy. Low to moderate DNA damage triggers pADPr-dependent DNA repair. In the context of excessive DNA damage, however, PARP1 hyperactivation leads to extended pADPr synthesis and extensive NAD + consumption 8,13,14 . Depending on the cellular context, this intense pADPr synthesis can induce cell death through several mechanisms. Long and branched pADPr (60mers and longer) can directly trigg...

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Section: How To Best Target Parps For Therapy?mentioning

confidence: 99%

PARP inhibition: PARP1 and beyond

et al. 2010

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“…On theoretical grounds PARP1 may be indirectly inhibited by depleting NAD + , the substrate of PARylation. 131 Nonetheless, the use of pharmacological inhibitors of the catalytic activity of PARP1 and PARP2 (hereafter referred to as PARP inhibitors for the sake of simplicity), including olaparib (also known as AZD2281), 132 rucaparib (also known as AG-014699), 133 veliparib (also known as ABT-888), 134 8983), 139 E7016 (also known as GPI21016), 140 and INO-1001, 141 has been the most explored approach in the context of cancer therapy. 6,12,16,75,[142][143][144][145][146][147] Over the last 40 years, two main anticancer strategies have been pursued, both based on the role of PARP1 in repairing DNA lesions.…”

Section: Parp1 In Cancer Therapymentioning

confidence: 97%

Trial watch – inhibiting PARP enzymes for anticancer therapy

Sistigu¹,

Manic²,

Obrist

et al. 2015

Molecular & Cellular Oncology

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Poly(ADP-ribose) polymerases (PARPs) are a members of family of enzymes that catalyze poly(ADP-ribosyl)ation (PARylation) and/or mono(ADP-ribosyl)ation (MARylation), two post-translational protein modifications involved in crucial cellular processes including (but not limited to) the DNA damage response (DDR). PARP1, the most abundant family member, is a nuclear protein that is activated upon sensing distinct types of DNA damage and contributes to their resolution by PARylating multiple DDR players. Recent evidence suggests that, along with DDR, activated PARP1 mediates a series of prosurvival and proapoptotic processes aimed at preserving genomic stability. Despite this potential oncosuppressive role, upregulation and/or overactivation of PARP1 or other PARP enzymes has been reported in a variety of human neoplasms. Over the last few decades, several pharmacologic inhibitors of PARP1 and PARP2 have been assessed in preclinical and clinical studies showing potent antineoplastic activity, particularly against homologous recombination (HR)-deficient ovarian and breast cancers. In this Trial Watch, we describe the impact of PARP enzymes and PARylation in cancer, discuss the mechanism of cancer cell killing by PARP1 inactivation, and summarize the results of recent clinical studies aimed at evaluating the safety and therapeutic profile of PARP inhibitors in cancer patients.

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“…One of the biggest obstacles, which must be faced in the successful translation of PARPi into the clinic as an anti-cancer therapy, is frequently observed tumor resistance. The most well-known mechanism of DNA repair developed by tumor cells is the restoration of HR activity (Noordermeer and van Attikum, 2019). The mechanisms responsible for this are: recreation of BRCA1/ 2 activity, observed in clinical trials in patients with BRCA1/2m cancers (Kondrashova et al, 2017) (reverse mutations (Domchek, 2017) or gene fusion under the transcriptional control of heterologous promoter (Ter Brugge et al, 2016)) and suppression of NHEJ (caused (Hurley et al, 2019).…”

Section: Parp Inhibitors-resisitancementioning

confidence: 99%

“…PARP proteins were discovered in the early 1960s by Chambon et al (1963) . Subsequent research showed that PARP family takes part in several cellular processes ( Krishnakumar and Kraus, 2010 ), the most intriguing being the interaction with DNA ( Nobori et al, 1989 ), which contributes to cellular recovery from DNA damage ( Durkacz et al, 1980 ).…”

Section: Parp Enzymes—structure and Mechanism Of Actionmentioning

confidence: 99%

The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

Hunia

Gawalski

Szredzka

et al. 2022

Front. Mol. Biosci.

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DNA damage response (DDR) deficiencies result in genome instability, which is one of the hallmarks of cancer. Poly (ADP-ribose) polymerase (PARP) enzymes take part in various DDR pathways, determining cell fate in the wake of DNA damage. PARPs are readily druggable and PARP inhibitors (PARPi) against the main DDR-associated PARPs, PARP1 and PARP2, are currently approved for the treatment of a range of tumor types. Inhibition of efficient PARP1/2-dependent DDR is fatal for tumor cells with homologous recombination deficiencies (HRD), especially defects in breast cancer type 1 susceptibility protein 1 or 2 (BRCA1/2)-dependent pathway, while allowing healthy cells to survive. Moreover, PARPi indirectly influence the tumor microenvironment by increasing genomic instability, immune pathway activation and PD-L1 expression on cancer cells. For this reason, PARPi might enhance sensitivity to immune checkpoint inhibitors (ICIs), such as anti-PD-(L)1 or anti-CTLA4, providing a rationale for PARPi-ICI combination therapies. In this review, we discuss the complex background of the different roles of PARP1/2 in the cell and summarize the basics of how PARPi work from bench to bedside. Furthermore, we detail the early data of ongoing clinical trials indicating the synergistic effect of PARPi and ICIs. We also introduce the diagnostic tools for therapy development and discuss the future perspectives and limitations of this approach.

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Poly(ADP-ribose) polymerase inhibits DNA synthesis initiation in the absence of NAD+

Cited by 11 publications

References 26 publications

PARP inhibition: PARP1 and beyond

PARP inhibition: PARP1 and beyond

Trial watch – inhibiting PARP enzymes for anticancer therapy

The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

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