scholarly journals Investigation of the Complexes Formed between PARP1 Inhibitors and PARP1 G-Quadruplex at the Gene Promoter Region

2021 ◽  
Vol 22 (16) ◽  
pp. 8737
Author(s):  
Sabrina Dallavalle ◽  
Salvatore Princiotto ◽  
Luce M. Mattio ◽  
Roberto Artali ◽  
Loana Musso ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Promoter Region ◽  
Gene Promoter ◽  
Parp Inhibition ◽  
Potential Binding ◽  
G Quadruplex ◽  
Parp1 Inhibitors ◽  
Tumoral Cells ◽  
Gene Promoter Region

DNA repair inhibitors are one of the latest additions to cancer chemotherapy. In general, chemotherapy produces DNA damage but tumoral cells may become resistant if enzymes involved in DNA repair are overexpressed and are able to reverse DNA damage. One of the most successful drugs based on modulating DNA repair are the poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. Several PARP1 inhibitors have been recently developed and approved for clinical treatments. We envisaged that PARP inhibition could be potentiated by simultaneously modulating the expression of PARP 1 and the enzyme activity, by a two-pronged strategy. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter has been recently identified. In this study, we explored the potential binding of clinically approved PARP1 inhibitors to the G-quadruplex structure found at the gene promoter region. The results obtained by NMR, CD, and fluorescence titration confirmed by molecular modeling demonstrated that two out the four PARP1 inhibitors studied are capable of forming defined complexes with the PARP1 G-quadruplex. These results open the possibility of exploring the development of better G-quadruplex binders that, in turn, may also inhibit the enzyme.

scholarly journals Site-specific base changes in the coding or promoter region of the human β- and γ-globin genes by single-stranded oligonucleotides

2005 ◽  
Vol 390 (1) ◽  
pp. 253-261 ◽  
Author(s):  
Wenxuan Yin ◽  
Betsy T. Kren ◽  
Clifford J. Steer
Keyword(s):  
Dna Repair ◽  
Sickle Cell ◽  
Promoter Region ◽  
Mammalian Cells ◽  
Globin Gene ◽  
Point Mutations ◽  
Gene Promoter ◽  
Globin Genes ◽  
Site Specific ◽  
Gene Promoter Region

SSOs (single-stranded oligonucleotides) can mediate site-specific alteration of base-pairs in episomal and chromosomal target genes in mammalian cells. The TNE (targeted nucleotide exchange) can result in either repair or mutation of a gene sequence and is mediated through endogenous DNA repair pathway(s). Thus the approach provides a technique for the treatment of monogenic disorders associated with specific point mutations such as SCD (sickle cell disease). We studied the potential application of SSOs for SCD by introducing either an A to T substitution at the sixth codon of the human β-globin gene (sickle locus) or a C to G mutation at −202 of the Gγ-globin gene promoter region. The latter TNE is an alternative strategy to ameliorate the clinical manifestations of sickle cell anaemia by re-activating fetal haemoglobin gene expression in adult erythrocytes. A sensitive and valid PCR assay system was developed, which allows detection of point mutations as low as 0.01% at these sites. Using this system, TNE between 0.01 and 0.1% at the sickle locus or γ-globin gene promoter region was detected after transfection with SSOs in cultured human cell lines. TNE in the Gγ-globin promoter region exhibited varying degrees of strand bias that was dependent on SSO design and the cell's DNA mismatch repair activity. The results suggest that the endogenous DNA repair machinery may permit SSO correction of the sickle defect by modification of the β- and/or γ-globin genes.

scholarly journals Characterization of the human pleiotrophin gene. Promoter region and chromosomal localization.

1992 ◽  
Vol 267 (36) ◽  
pp. 26011-26016 ◽  
Author(s):  
Y.S. Li ◽  
R.M. Hoffman ◽  
M.M. Le Beau ◽  
R Espinosa ◽  
N.A. Jenkins ◽  
...  
Keyword(s):  
Promoter Region ◽  
Chromosomal Localization ◽  
Gene Promoter ◽  
Gene Promoter Region

CBIO-22. PARP INHIBITION SYNERGIZES WITH DNA DAMAGING DRUGS IN PEDIATRIC CNS TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi31-vi31
Author(s):  
Anna Laemmerer ◽  
Dominik Kirchhofer ◽  
Sibylle Madlener ◽  
Daniela Loetsch-Gojo ◽  
Carola Jaunecker ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Predictive Biomarkers ◽  
High Grade Glioma ◽  
Parp Inhibitors ◽  
Cns Tumors ◽  
Parp Inhibition ◽  
Tumor Subtypes ◽  
Synergistic Cytotoxicity ◽  
Anti Cancer

Abstract BACKGROUND Central nervous system (CNS) tumors are the second most common childhood cancer. Despite innovations in surgery and chemo-/radiotherapy, CNS tumors remain the major cause of cancer-related death in children. Previous sequencing analyses in a pediatric cancer cohort identified BRCA and DSB repair signatures as potentially targetable events. Based on these findings, we propose the use of PARP inhibitors (PARPi) for aggressive CNS tumor subtypes, including high-grade glioma (HGG), medulloblastoma (MB) and ependymoma (EPN). METHODS We tested multiple PARPi in tumor cell lines (n=8) as well as primary patient-derived models (n=11) of pediatric HGG, MB, EPN and atypical teratoid/rhabdoid tumors (ATRTs). Based on PARPi sensitivity, selected models were further exposed to a combination of PARPi and DNA-damaging/modifying agents. The mode of action was investigated using Western blot and flow cytometry. RESULTS We show that a fraction of pediatric MB, EPN and ATRT demonstrate sensitivity towards PARP inhibition, which is paralleled by susceptibility to the DNA damaging drugs cisplatin and irinotecan. Interestingly, talazoparib, the most potent PARPi, showed synergistic cytotoxicity with DNA-damaging/modifying drugs. In addition, cell cycle blockade and increased DNA damage combined with reduced DNA repair signaling, such as activation of the ATR/Chk1 pathway were observed. Corroboratively, talazoparib exhibited a synergistic anti-cancer effect in combination with inhibitors of ATR, a major regulator of DNA damage response. CONCLUSION/OUTLOOK To sum up, we demonstrate that PARP inhibition synergizes with DNA damaging anti-cancer compounds or DNA repair inhibitors and, thus, represents a promising therapeutic strategy for a defined subgroup of pediatric high-risk CNS tumors patients. More in depth characterization of the underlying molecular events will most likely allow the identification of predictive biomarkers for most efficient implementation of this strategy into clinical application.

scholarly journals Polymorphism in SNAP29 gene promoter region associated with schizophrenia

2001 ◽  
Vol 6 (2) ◽  
pp. 193-201 ◽  
Author(s):  
T Saito ◽  
F Guan ◽  
D F Papolos ◽  
N Rajouria ◽  
C S J Fann ◽  
...  
Keyword(s):  
Promoter Region ◽  
Gene Promoter ◽  
Gene Promoter Region

scholarly journals Polymorphisms of the ELANE Gene Promoter Region in End-Stage Chronic Kidney Disease Patients

Genes ◽  
2016 ◽  
Vol 7 (5) ◽  
pp. 17
Author(s):  
Rafael Fernandes ◽  
Bruno Freitas ◽  
Vasco Miranda ◽  
Elísio Costa ◽  
Alice Santos-Silva ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Promoter Region ◽  
Gene Promoter ◽  
End Stage ◽  
Gene Promoter Region
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