D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming
Abstract Cancer-associated mutations in IDH are associated with multiple types of human malignancies, which exhibit distinctive metabolic reprogramming, production of oncometabolite D-2-HG, and shifted epigenetic landscape. IDH mutated malignancies are signatured with “BRCAness”, highlighted with th...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56781-2 |
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| author | Fengchao Lang Karambir Kaur Haiqing Fu Javeria Zaheer Diego Luis Ribeiro Mirit I. Aladjem Chunzhang Yang |
| author_facet | Fengchao Lang Karambir Kaur Haiqing Fu Javeria Zaheer Diego Luis Ribeiro Mirit I. Aladjem Chunzhang Yang |
| author_sort | Fengchao Lang |
| collection | DOAJ |
| description | Abstract Cancer-associated mutations in IDH are associated with multiple types of human malignancies, which exhibit distinctive metabolic reprogramming, production of oncometabolite D-2-HG, and shifted epigenetic landscape. IDH mutated malignancies are signatured with “BRCAness”, highlighted with the sensitivity to DNA repair inhibitors and genotoxic agents, although the underlying molecular mechanism remains elusive. In the present study, we demonstrate that D-2-HG impacts the chromatin conformation adjustments, which are associated with DNA repair process. Mechanistically, D-2-HG diminishes the chromatin interactions in the DNA damage regions via revoking CTCF binding. The hypermethylation of cytosine, resulting from the suppression of TET1 and TET2 activities by D-2-HG, contributes to the dissociation of CTCF from DNA damage regions. CTCF depletion leads to the disruption of chromatin organization around the DNA damage sites, which abolishes the recruitment of essential DNA damage repair proteins BRCA2 and RAD51, as well as impairs homologous repair in the IDH mutant cancer cells. These findings provide evidence that CTCF-mediated chromatin interactions play a key role in DNA damage repair proceedings. Oncometabolites jeopardize genome stability and DNA repair by affecting high-order chromatin structure. |
| format | Article |
| id | doaj-art-46f5bb51da0d4e78b507c9fb0ad77f83 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-46f5bb51da0d4e78b507c9fb0ad77f832025-02-09T12:43:56ZengNature PortfolioNature Communications2041-17232025-02-0116111310.1038/s41467-025-56781-2D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogrammingFengchao Lang0Karambir Kaur1Haiqing Fu2Javeria Zaheer3Diego Luis Ribeiro4Mirit I. Aladjem5Chunzhang Yang6Neuro-Oncology Branch, Center for Cancer Research, National Cancer InstituteNeuro-Oncology Branch, Center for Cancer Research, National Cancer InstituteDevelopmental Therapeutic Branch, Center for Cancer Research, National Cancer InstituteNeuro-Oncology Branch, Center for Cancer Research, National Cancer InstituteNeuro-Oncology Branch, Center for Cancer Research, National Cancer InstituteDevelopmental Therapeutic Branch, Center for Cancer Research, National Cancer InstituteNeuro-Oncology Branch, Center for Cancer Research, National Cancer InstituteAbstract Cancer-associated mutations in IDH are associated with multiple types of human malignancies, which exhibit distinctive metabolic reprogramming, production of oncometabolite D-2-HG, and shifted epigenetic landscape. IDH mutated malignancies are signatured with “BRCAness”, highlighted with the sensitivity to DNA repair inhibitors and genotoxic agents, although the underlying molecular mechanism remains elusive. In the present study, we demonstrate that D-2-HG impacts the chromatin conformation adjustments, which are associated with DNA repair process. Mechanistically, D-2-HG diminishes the chromatin interactions in the DNA damage regions via revoking CTCF binding. The hypermethylation of cytosine, resulting from the suppression of TET1 and TET2 activities by D-2-HG, contributes to the dissociation of CTCF from DNA damage regions. CTCF depletion leads to the disruption of chromatin organization around the DNA damage sites, which abolishes the recruitment of essential DNA damage repair proteins BRCA2 and RAD51, as well as impairs homologous repair in the IDH mutant cancer cells. These findings provide evidence that CTCF-mediated chromatin interactions play a key role in DNA damage repair proceedings. Oncometabolites jeopardize genome stability and DNA repair by affecting high-order chromatin structure.https://doi.org/10.1038/s41467-025-56781-2 |
| spellingShingle | Fengchao Lang Karambir Kaur Haiqing Fu Javeria Zaheer Diego Luis Ribeiro Mirit I. Aladjem Chunzhang Yang D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming Nature Communications |
| title | D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming |
| title_full | D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming |
| title_fullStr | D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming |
| title_full_unstemmed | D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming |
| title_short | D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming |
| title_sort | d 2 hydroxyglutarate impairs dna repair through epigenetic reprogramming |
| url | https://doi.org/10.1038/s41467-025-56781-2 |
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