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Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting tumor mutation burden

UID: 10937

Author(s): Schvartzman, Juan-Manuel*, Koche, Richard Patrick*, Thompson, Craig B.* * MSK affiliated

Description
Summary from GEO:

"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 from GEO:

"Repli-seq in IDH2 wild type and R172K mutant U2OS and RKO cell lines."
Subject of Study
Homo sapiens
Subject(s)
DNA Replication
Heterochromatin
Isocitrate Dehydrogenase
Poly ADP Ribosylation
Poly(ADP-ribose) Polymerase Inhibitors
Access via GEO


Accession #: GSE211592

Access via BioProject


Accession #: PRJNA870962

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus, BioProject, and SRA databases provide open access to these files.
Associated Publications
Schvartzman J, Forsyth G, Walch H, Chatila W, Taglialatela A, Lee B, Zhu X, Gershik S, Cimino F, Santella A, Menghrajani K, Ciccia A, Koche R, Sánchez-Vega F, Zha S, Thompson C. Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting homologous recombination. Molecular Cell. 2023; 83(13):2347-2356.e8.
Equipment Used
Illumina NextSeq 500
Dataset Format(s)
TAR, BEDGRAPH
Dataset Size
10.5 MB (TAR), 5.13 MB (12 BEDGRAPH files)
Data Catalog Record Updated
2023-10-13