Role of PARP1 in DNA repair: DNA damage activates PARP1 enzyme resulting in homodimerization of the enzyme. Then the DNA binding domain of PARP-1 binds to the damaged DNA and consumes Nicotinamide Adenine Dinucleotide (NAD + ) as a 

Contexts in source publication

Context 1

... is a chromatin-bound nuclear enzyme involved in the detection and damaged-DNA repair pathway, importantly the base excision repair (BER) of single strand breaks (SSBs). [2] PARP constitute a family of cell signaling enzymes which catalyzes the poly(ADP- ribosyl)ation of DNA-binding proteins and have emerged as critical regulatory components of the immediate cellular response to DNA damage ( Figure 1). This protein plays a key role in maintaining genome integrity through modulation of multiple cellular responses (including base excision repair, necrosis and apoptosis) in the face of genotoxic stress [3,4]. ...

Context 2

... poly (ADP) ribosylation, PARP-1 utilizes NAD + to synthesize poly (ADP)-ribose units either on itself or on a variety of nuclear target proteins such as histones, topoisomerases, DNA polymerases and DNA ligases (Figure 1). This results in highly negative charged nuclear proteins, which in turn leads to the unwinding and repair of the damaged DNA through the base excision repair (BER) pathway. ...

Context 3

... American Cancer Society (ACS) recently estimated that over 600,000 of Americans are projected to die, whereas 1600,000 new cancer cases would be diagnosed in 2013. Recent discoveries of novel-targeted therapies have revolutionized the oncology treatment in the last decade. Traditional anticancer agents were limited due to their non-selectivity towards cancer cells, drug resistance and that they had a very narrow therapeutic window, which limited their use due to unfavorable toxicities to normal cells. Therefore, novel-targeted agents have proved beneficial and have significantly improved the patient survival. This has also been possible due to our better understanding of drug-drug interactions and considerably improved efficacy of clinical anticancer agents when used in combination chemotherapy. The objective has been to multi- target the cancer cells to limit development of resistance, while designing compounds that possess maximum activity with the least or no cross-resistance, and that in conjunction the two agents will demonstrate synergy, or improved effectiveness than when they were used as monotherapies. Combining Poly(ADP- ribose)polymerase-1 (PARP-1) inhibitors with cytotoxic agents such as chemotherapy or radiation therapy is synergistic in many preclinical models. With novel and selective mechanisms of action, PARP-1 inhibitors have moved from the laboratory to the clinic in just the last few years. PARP exist in 17 isoforms, and have been characterized based on sequence homology within the catalytic domain[1] and amongst them, PARP-1 is the first to be characterized and perhaps best known member of the PARP family. PARP-1 accounts for more than 90% of cellular PARP activity. PARP-1 is a chromatin-bound nuclear enzyme involved in the detection and damaged-DNA repair pathway, importantly the base excision repair (BER) of single strand breaks (SSBs).[2] PARP constitute a family of cell signaling enzymes which catalyzes the poly(ADP- ribosyl)ation of DNA-binding proteins and have emerged as critical regulatory components of the immediate cellular response to DNA damage (Figure 1). This protein plays a key role in maintaining genome integrity through modulation of multiple cellular responses (including base excision repair, necrosis and apoptosis) in the face of genotoxic stress [3,4]. ADP-ribosylation reactions are involved in many physiological and pathophysiological processes, including inter- and intracellular signaling, transcription, DNA repair pathways, cell cycle regulation, and mitosis, as well as necrosis and apoptosis [5]. PARP-1, the founding member of the PARP family, is a molecular sensor of DNA breaks, playing a key role in the spatial and temporal organization of break repair through the local synthesis of poly (ADP-ribose) (PAR) at damaged sites, and were expressed at high levels throughout the embryo. Only Parp-1 and Parp-2 have been shown to be activated by DNA strand breaks [6]. PARP-9 [B-aggressive lymphoma-1 (BAL-1), macro PARP] has recently been discovered in patients with certain types of diffuse large B-cell lymphomas (DLBCL) and described as a new nuclear protein encoded by the BAL gene, which is expressed in the thymus and specific regions (neuroepithelium) of the brain and gut [7]. PARP-14 is weakly expressed, mainly in the thymus during development and in adulthood, it is essentially co-expressed with PARP-9. During poly (ADP) ribosylation, PARP-1 utilizes NAD + to synthesize poly (ADP)-ribose units either on itself or on a variety of nuclear target proteins such as histones, topoisomerases, DNA polymerases and DNA ligases (Figure 1). This results in highly negative charged nuclear proteins, which in turn leads to the unwinding and repair of the damaged DNA through the base excision repair (BER) pathway. PARP inhibitors offer potential therapies for a wide variety of diseases such as inflammatory conditions, diabetes complications, neurological diseases, stroke and myocardial infarction [8-11]. However, presently, the most prominent clinical role for PARP inhibitors lies within the field of oncology especially the breast cancer susceptibility proteins (BRCA) resistant breast and ovarian cancers. Inhibition of PARP sensitizes tumor cells to cytotoxic drugs that induce DNA damage that would normally be repaired through the BER pathway. PARP-1 inhibitors have consistently demonstrated potentiating effects on the DNA- alkylating agent temozolomide (TMZ) in preclinical studies, including experimental models of solid tumors such as glioma, melanoma, colorectal, and breast cancer. PARP-1 inhibitors have been demonstrated to sensitize tumors to DNA-alkylating agents (TMZ The majority and cyclophosphamide) of the inhibitors as of well PARP-1 as topoisomerase contain either I poisons free or such cyclic as amide camptothecin in their structures and irinotecan (Figure 2). (CPT-11) Molecular [4,12-15]. insight The PARP-1 between counteracts the PARP-1 camptothecin and the inhibitors action has by been facilitating shown resealing to bind of with DNA the catalytic strand breaks.[14,16] domain of PARP-1 Hence, with PARP-1 “conserved” inhibition and hampers “unconserved” topoisomerase-I interactions. activity Conserved favoring interactions the toxic effects include of two the enzyme lone pair poisons. electrons Indeed, of the preclinical carbonyl oxygen in vivo atom studies of amide have shown forms that two critical the combination hydrogen bonds, of the one PARP-1 with the inhibitor side chain CEP-6800 hydroxyl and of CPT-11 significantly reduces tumor volume of HT-29 colon carcinoma subcutaneous xenografts compared to CPT-11 monotherapy [13]. TMZ is a second-generation DNA-alkylating agent and although TMZ was not effective in a phase II clinical trial against metastatic breast cancer as a monotherapy [17]. It is currently in phase II clinical trial in combination with the PARP-1 inhibitor AG014699 from Pfizer [18,19] and demonstrated promising results in a phase I trial [19]. The majority of the inhibitors of PARP-1 contain either free or cyclic amide in their structures (Figure 2). Molecular insight between the PARP-1 and the inhibitors has been shown to bind with the catalytic domain of PARP-1 with “conserved” and “unconserved” interactions. Conserved interactions include two lone pair electrons of the carbonyl oxygen atom of amide forms two critical hydrogen bonds, one with the side chain hydroxyl of Ser904 and the second with the backbone - NH of Gly863 (Figure 3). The - NH of the amide usually are involved in hydrogen bonding interaction with the backbone carbonyl oxygen atom of Gly863. Electron rich phenol side chain of Tyr907 is found to have critical role in the interactions with phenyl portion of the ligands in face-to-face, π - π interactions as shown in our previous published report [20]. Unconserved interactions include the other interactions present with the inhibitors based on their structures. Thus there is sufficient preclinical and clinical evidence to support the notion that combined inhibition of PARP enzyme in conjunction with ...

Context 4

... American Cancer Society (ACS) recently estimated that over 600,000 of Americans are projected to die, whereas 1600,000 new cancer cases would be diagnosed in 2013. Recent discoveries of novel-targeted therapies have revolutionized the oncology treatment in the last decade. Traditional anticancer agents were limited due to their non-selectivity towards cancer cells, drug resistance and that they had a very narrow therapeutic window, which limited their use due to unfavorable toxicities to normal cells. Therefore, novel-targeted agents have proved beneficial and have significantly improved the patient survival. This has also been possible due to our better understanding of drug-drug interactions and considerably improved efficacy of clinical anticancer agents when used in combination chemotherapy. The objective has been to multi- target the cancer cells to limit development of resistance, while designing compounds that possess maximum activity with the least or no cross-resistance, and that in conjunction the two agents will demonstrate synergy, or improved effectiveness than when they were used as monotherapies. Combining Poly(ADP- ribose)polymerase-1 (PARP-1) inhibitors with cytotoxic agents such as chemotherapy or radiation therapy is synergistic in many preclinical models. With novel and selective mechanisms of action, PARP-1 inhibitors have moved from the laboratory to the clinic in just the last few years. PARP exist in 17 isoforms, and have been characterized based on sequence homology within the catalytic domain[1] and amongst them, PARP-1 is the first to be characterized and perhaps best known member of the PARP family. PARP-1 accounts for more than 90% of cellular PARP activity. PARP-1 is a chromatin-bound nuclear enzyme involved in the detection and damaged-DNA repair pathway, importantly the base excision repair (BER) of single strand breaks (SSBs).[2] PARP constitute a family of cell signaling enzymes which catalyzes the poly(ADP- ribosyl)ation of DNA-binding proteins and have emerged as critical regulatory components of the immediate cellular response to DNA damage (Figure 1). This protein plays a key role in maintaining genome integrity through modulation of multiple cellular responses (including base excision repair, necrosis and apoptosis) in the face of genotoxic stress [3,4]. ADP-ribosylation reactions are involved in many physiological and pathophysiological processes, including inter- and intracellular signaling, transcription, DNA repair pathways, cell cycle regulation, and mitosis, as well as necrosis and apoptosis [5]. PARP-1, the founding member of the PARP family, is a molecular sensor of DNA breaks, playing a key role in the spatial and temporal organization of break repair through the local synthesis of poly (ADP-ribose) (PAR) at damaged sites, and were expressed at high levels throughout the embryo. Only Parp-1 and Parp-2 have been shown to be activated by DNA strand breaks [6]. PARP-9 [B-aggressive lymphoma-1 (BAL-1), macro PARP] has recently been discovered in patients with certain types of diffuse large B-cell lymphomas (DLBCL) and described as a new nuclear protein encoded by the BAL gene, which is expressed in the thymus and specific regions (neuroepithelium) of the brain and gut [7]. PARP-14 is weakly expressed, mainly in the thymus during development and in adulthood, it is essentially co-expressed with PARP-9. During poly (ADP) ribosylation, PARP-1 utilizes NAD + to synthesize poly (ADP)-ribose units either on itself or on a variety of nuclear target proteins such as histones, topoisomerases, DNA polymerases and DNA ligases (Figure 1). This results in highly negative charged nuclear proteins, which in turn leads to the unwinding and repair of the damaged DNA through the base excision repair (BER) pathway. PARP inhibitors offer potential therapies for a wide variety of diseases such as inflammatory conditions, diabetes complications, neurological diseases, stroke and myocardial infarction [8-11]. However, presently, the most prominent clinical role for PARP inhibitors lies within the field of oncology especially the breast cancer susceptibility proteins (BRCA) resistant breast and ovarian cancers. Inhibition of PARP sensitizes tumor cells to cytotoxic drugs that induce DNA damage that would normally be repaired through the BER pathway. PARP-1 inhibitors have consistently demonstrated potentiating effects on the DNA- alkylating agent temozolomide (TMZ) in preclinical studies, including experimental models of solid tumors such as glioma, melanoma, colorectal, and breast cancer. PARP-1 inhibitors have been demonstrated to sensitize tumors to DNA-alkylating agents (TMZ The majority and cyclophosphamide) of the inhibitors as of well PARP-1 as topoisomerase contain either I poisons free or such cyclic as amide camptothecin in their structures and irinotecan (Figure 2). (CPT-11) Molecular [4,12-15]. insight The PARP-1 between counteracts the PARP-1 camptothecin and the inhibitors action has by been facilitating shown resealing to bind of with DNA the catalytic strand breaks.[14,16] domain of PARP-1 Hence, with PARP-1 “conserved” inhibition and hampers “unconserved” topoisomerase-I interactions. activity Conserved favoring interactions the toxic effects include of two the enzyme lone pair poisons. electrons Indeed, of the preclinical carbonyl oxygen in vivo atom studies of amide have shown forms that two critical the combination hydrogen bonds, of the one PARP-1 with the inhibitor side chain CEP-6800 hydroxyl and of CPT-11 significantly reduces tumor volume of HT-29 colon carcinoma subcutaneous xenografts compared to CPT-11 monotherapy [13]. TMZ is a second-generation DNA-alkylating agent and although TMZ was not effective in a phase II clinical trial against metastatic breast cancer as a monotherapy [17]. It is currently in phase II clinical trial in combination with the PARP-1 inhibitor AG014699 from Pfizer [18,19] and demonstrated promising results in a phase I trial [19]. The majority of the inhibitors of PARP-1 contain either free or cyclic amide in their structures (Figure 2). Molecular insight between the PARP-1 and the inhibitors has been shown to bind with the catalytic domain of PARP-1 with “conserved” and “unconserved” interactions. Conserved interactions include two lone pair electrons of the carbonyl oxygen atom of amide forms two critical hydrogen bonds, one with the side chain hydroxyl of Ser904 and the second with the backbone - NH of Gly863 (Figure 3). The - NH of the amide usually are involved in hydrogen bonding interaction with the backbone carbonyl oxygen atom of Gly863. Electron rich phenol side chain of Tyr907 is found to have critical role in the interactions with phenyl portion of the ligands in face-to-face, π - π interactions as shown in our previous published report [20]. Unconserved interactions include the other interactions present with the inhibitors based on their structures. Thus there is sufficient preclinical and clinical evidence to support the notion that combined inhibition of PARP enzyme in conjunction with DNA-damage will significantly benefit tumor patients. Thus, development of PARP inhibitors could potentially be useful to gain disease control without potentiating side effects and is an interesting research area providing innovative cancer treatment opportunities. There A number is a great of unanswered interest for questions the clinical with development PARP utility of in PARP-1 clinics inhibitors need to be as addressed. a monotherapy For example, against how BRCA-associated are the PARP ovarian activated? or breast What are cancer the mechanisms or in combination for their cardio- therapy and with neuro-protection other SSBs targeting roles observed chemotherapeutic earlier? Does the agents PARP-1 in TNBC. sensitize However, cancer cells a number due to their of limitations effects on inflammatory need to be carefully pathways? addressed, The downstream before this signaling can be of successfully PARP-1 mediated used in cascade the clinics. i.e. range It is important of signaling to realize molecules that recruited PARP by on PARP-1 a continuous is not clear. basis One monitors may also DNA need mutations; to identify clinical therefore conditions PARP inhibition and consider may signaling lead to secondary pathways malignancy involved, in similar addition to to BRCA pathogenetic mutations, and due biochemical to its inability features to repair that sensitizes normal the cellular tumors processes. to PARP In addition, inhibitors. it For is becoming example, clearer PARP-1 that ...