PRICKLE4 Underlies IDH mutant Tumors Resistance against PARP Inhibition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1050787 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27166513_1.fastq.gz | Fastqsanger.gz | |||
| SRR27166513_2.fastq.gz | Fastqsanger.gz | |||
| SRR27166514_1.fastq.gz | Fastqsanger.gz | |||
| SRR27166514_2.fastq.gz | Fastqsanger.gz | |||
| SRR27166515_1.fastq.gz | Fastqsanger.gz |
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Project description:Oncogenic mutations in the metabolic enzyme isocitrate dehydrogenase 1 and 2 (IDH1/2) have been found in a number of liquid and solid tumors. Their pathogenic mechanism of action involves production of 2-hydroxyglutarate (2HG), an oncometabolite that acts in part by inhibiting members of a family of dioxygenases that modulate chromatin dynamics. Recent work has suggested that mutant IDH (mIDH) and 2HG also impact sensitivity to inhibitors of poly-ADP ribose polymerases (PARP) but the molecular basis for this sensitivity is unclear. Unlike PARP inhibitor-sensitive BRCA1/2 tumors which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack mutational signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to heterochromatin-dependent slowing of DNA replication and increased replication stress, resulting in DNA double strand breaks. This replicative stress manifests as replication fork slowing but the breaks are repaired without a significant increase in the cellular mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-ADP ribosylation. Treatment with PARP inhibitors restores replication fork speed but results in incomplete repair of DNA breaks. These findings provide evidence of a requirement for PARP in the replication of heterochromatin and further validate PARP as a potential therapeutic target in IDH-mutant tumors.
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Project description:Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in liver. Microarray analysis of PARP-2 knockdown HepG2 cells revealed the dysregulation of lipid and cholesterol metabolism genes. Induction of cholesterol biosynthesis genes stemmed from the enhanced expression of sterol-regulatory element binding protein (SREBP)-1. We revealed that PARP-2 is a suppressor of the SREBP-1 promoter, therefore ablation of PARP-2 induces SREBP-1 expression and consequently cholesterol synthesis. PARP-2-/- mice had higher SREBP-1 expression that was translated into enhanced hepatic and serum cholesterol levels. PARP-2 silencing was performed employing shPARP-2 (small hairpin) and scPARP-2 (scrambled) shRNA by lentiviral delivery (Sigma) using 40 MOI lentiviruses coding shRNA sequence against PARP-2.
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