Abstract:The PARP family consists of 17 members with diverse functions, including those related to cancer cells’ viability. Several PARP inhibitors are of great interest as innovative anticancer drugs, but they have low selectivity towards distinct PARP family members and exert serious adverse effects. We describe a family-wide study of the nicotinamide (NA) binding site, an important functional region in the PARP structure, using comparative bioinformatic analysis and molecular modeling. Mutations in the NA site and D… Show more
“…PARP1 is an abundant nuclear enzyme (1-2 million molecules per cell) and a nucleosome-binding protein localized in cell nuclei and involved in a variety of cellular processes including DNA repair, chromatin organization and transcription [1][2][3][4].…”
Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme involved in DNA repair, chromatin organization and transcription. During transcription initiation, PARP1 interacts with gene promoters where it binds to nucleosomes, replaces linker histone H1 and participates in gene regulation. However, the mechanisms of PARP1-nucleosome interaction remain unknown. Here, using spFRET microscopy, molecular dynamics and biochemical approaches we identified several different PARP1-nucleosome complexes and two types of PARP1 binding to mononucleosomes: at DNA ends and end-independent. Two or three molecules of PARP1 can bind to a nucleosome depending on the presence of linker DNA and can induce reorganization of the entire nucleosome that is independent of catalytic activity of PARP1. Nucleosome reorganization depends upon binding of PARP1 to nucleosomal DNA, likely near the binding site of linker histone H1. The data suggest that PARP1 can induce the formation of an alternative nucleosome state that is likely involved in gene regulation and DNA repair.
“…PARP1 is an abundant nuclear enzyme (1-2 million molecules per cell) and a nucleosome-binding protein localized in cell nuclei and involved in a variety of cellular processes including DNA repair, chromatin organization and transcription [1][2][3][4].…”
Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme involved in DNA repair, chromatin organization and transcription. During transcription initiation, PARP1 interacts with gene promoters where it binds to nucleosomes, replaces linker histone H1 and participates in gene regulation. However, the mechanisms of PARP1-nucleosome interaction remain unknown. Here, using spFRET microscopy, molecular dynamics and biochemical approaches we identified several different PARP1-nucleosome complexes and two types of PARP1 binding to mononucleosomes: at DNA ends and end-independent. Two or three molecules of PARP1 can bind to a nucleosome depending on the presence of linker DNA and can induce reorganization of the entire nucleosome that is independent of catalytic activity of PARP1. Nucleosome reorganization depends upon binding of PARP1 to nucleosomal DNA, likely near the binding site of linker histone H1. The data suggest that PARP1 can induce the formation of an alternative nucleosome state that is likely involved in gene regulation and DNA repair.
“…2 ) that inhibited PARP10 [ 50 , 51 ]. According to the literature, the amino acids His887, Gly888, Asn910, Ala911, Tyr914, Tyr919, Ala921, Leu926, Ser927, and Tyr932 are the most important ones in the PARP10 active site [ 52 , 53 ]. Fig.…”
Background
Cancer is the most cause of morbidity and mortality, and a major public health problem worldwide. In this context, two series of quinazolinone 5a–e and dihydroquinazolinone 10a–f compounds were designed, synthesized as cytotoxic agents.
Methodology
All derivatives (5a–e and 10a–f) were synthesized via straightforward pathways and elucidated by FTIR, 1H-NMR, CHNS elemental analysis, as well as the melting point. All the compounds were evaluated for their in vitro cytotoxicity effects using the MTT assay against two human cancer cell lines (MCF-7 and HCT-116) using doxorubicin as the standard drug. The test derivatives were additionally docked into the PARP10 active site using Gold software.
Results and discussion
Most of the synthesized compounds, especially 5a and 10f were found to be highly potent against both cell lines. Synthesized compounds demonstrated IC50 in the range of 4.87–205.9 μM against HCT-116 cell line and 14.70–98.45 μM against MCF-7 cell line compared with doxorubicin with IC50 values of 1.20 and 1.08 μM after 72 h, respectively, indicated the plausible activities of the synthesized compounds.
Conclusion
The compounds quinazolinone 5a–e and dihydroquinazolinone 10a–f showed potential activity against cancer cell lines which can lead to rational drug designing of the cytotoxic agents.
“…The poly(ADP-ribose) polymerase (PArP) family encompasses 17 enzymes that assume a critical role in safeguarding DnA replication forks and orchestrating DnA repair processes through various pathways, including single-strand DnA breaks repair, homologous recombination, nucleotide excision repair (nEr), and alternative nonhomologous end joining (nHEJ) [22,23].…”
Purpose of the review: This comprehensive review aims to provide a summary of current research on the utilization of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in the treatment of ovarian cancer. The review aims to highlight the key findings from recent clinical trials and assess the potential of olaparib as a targeted therapy for improving the prognosis of ovarian cancer patients.
Recent findings: Ovarian cancer remains a significant global health concern with high mortality rates. While optimal debulking surgery and platinum-based chemotherapy are the standard treatments, the recurrence rates remain substantial. The emergence of PARP inhibitors, particularly olaparib, has introduced a novel therapeutic approach that targets the genomic instability and DNA repair mechanisms in cancer cells. Notable clinical trials, such as SOLO1, SOLO2, and PAOLA-1, have demonstrated the effectiveness of olaparib in significantly improving progression-free survival, particularly in patients with BRCA mutations or homologous recombination deficiency. Additionally, combination therapies involving olaparib, such as those with bevacizumab or entinostat, have shown promising results.
Summary: The utilization of olaparib has brought about a paradigm shift in the treatment of ovarian cancer. Notably, it has shown significant improvements in progression-free survival and overall survival, particularly in patients with BRCA mutations or homologous recombination deficiency. The exploration of olaparib through various clinical trials and combination therapies continues to provide valuable insights and offer new prospects for ovarian cancer patients. Moreover, the growing understanding of PARP inhibitors holds the potential for further advancements in the prognosis of patients with this formidable condition.
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