{"database":"ENA","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Fastqsanger.gz":["ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/070/SRR21131570/SRR21131570_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/062/SRR21131562/SRR21131562_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/058/SRR21131558/SRR21131558_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/066/SRR21131566/SRR21131566_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/073/SRR21131573/SRR21131573_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/054/SRR21131554/SRR21131554_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/056/SRR21131556/SRR21131556_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/061/SRR21131561/SRR21131561_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/064/SRR21131564/SRR21131564_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/052/SRR21131552/SRR21131552_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/065/SRR21131565/SRR21131565_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/068/SRR21131568/SRR21131568_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/050/SRR21131550/SRR21131550_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/063/SRR21131563/SRR21131563_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/057/SRR21131557/SRR21131557_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/065/SRR21131565/SRR21131565_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/059/SRR21131559/SRR21131559_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/053/SRR21131553/SRR21131553_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/069/SRR21131569/SRR21131569_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/071/SRR21131571/SRR21131571_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/070/SRR21131570/SRR21131570_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/053/SRR21131553/SRR21131553_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/051/SRR21131551/SRR21131551_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/056/SRR21131556/SRR21131556_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/072/SRR21131572/SRR21131572_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/052/SRR21131552/SRR21131552_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/060/SRR21131560/SRR21131560_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/067/SRR21131567/SRR21131567_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/068/SRR21131568/SRR21131568_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/059/SRR21131559/SRR21131559_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/050/SRR21131550/SRR21131550_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/062/SRR21131562/SRR21131562_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/055/SRR21131555/SRR21131555_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/071/SRR21131571/SRR21131571_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/058/SRR21131558/SRR21131558_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/055/SRR21131555/SRR21131555_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/073/SRR21131573/SRR21131573_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/063/SRR21131563/SRR21131563_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/054/SRR21131554/SRR21131554_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/057/SRR21131557/SRR21131557_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/072/SRR21131572/SRR21131572_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/069/SRR21131569/SRR21131569_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/051/SRR21131551/SRR21131551_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/067/SRR21131567/SRR21131567_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/066/SRR21131566/SRR21131566_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/061/SRR21131561/SRR21131561_2.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/060/SRR21131560/SRR21131560_1.fastq.gz","ftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR211/064/SRR21131564/SRR21131564_2.fastq.gz"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"center_name":["Memorial Sloan Kettering Cancer Center"],"full_dataset_link":["https://www.ebi.ac.uk/ena/browser/view/PRJNA870962"],"scientific_name":["Homo sapiens"],"long_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. Overall design: Repli-seq in IDH2 wild type and R172K mutant U2OS and RKO cell lines."],"tag":["xref:PubMed:37311462"],"repository":["ENA"],"additional_accession":[]},"is_claimable":false,"name":"Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting tumor mutation burden","description":"Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting tumor mutation burden","dates":{"last_updated":"2025-09-24","first_public":"2023-08-30"},"accession":"PRJNA870962","cross_references":{"GEO":["GSE211592"],"taxon":["9606"],"PubMed":["37311462"]}}