CTCF prevents genomic instability by promoting homologous recombination-directed DNA double-strand break repair
| Autor: | Fengchao Lang, Danfeng Lu, Guijun Chen, Daohua Gong, Zhuoran Li, Liping Yang, Xin Li, Peng Shi, Jumin Zhou, Wenhai Zheng, Jinlin Fu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genome instability CCCTC-Binding Factor DNA repair RAD51 Bone Neoplasms Biology Genomic Instability 03 medical and health sciences Tumor Cells Cultured medicine Humans RNA Small Interfering Genetics Osteosarcoma Multidisciplinary 030102 biochemistry & molecular biology Recombinational DNA Repair Biological Sciences medicine.disease MDC1 030104 developmental biology CTCF Rad51 Recombinase Chromosome breakage Homologous recombination Nijmegen breakage syndrome DNA Damage |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:10912-10917 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1704076114 |
| Popis: | CTCF is an essential epigenetic regulator mediating chromatin insulation, long-range regulatory interactions, and the organization of large topological domains in the nucleus. Phenotypes of CTCF haploinsufficient mutations in humans, knockout in mice, and depletion in cells are often consistent with impaired genome stability, but a role of CTCF in genome maintenance has not been fully investigated. Here, we report that CTCF maintains genome stability, is recruited to sites of DNA damage, and promotes homologous recombination repair of DNA double-strand breaks (DSBs). CTCF depletion increased chromosomal instability, marked by chromosome breakage and end fusions, elevated genotoxic stress-induced genomic DNA fragmentation, and activated the ataxia telangiectasia mutated (ATM) kinase. We show that CTCF could be recruited to drug-induced 53BP1 foci and known fragile sites, as well as to I-SceI endonuclease-induced DSBs. Laser irradiation analysis revealed that this recruitment depends on ATM, Nijmegen breakage syndrome (NBS), and the zinc finger DNA-binding domain of CTCF. We demonstrate that CTCF knockdown impaired homologous recombination (HR) repair of DSBs. Consistent with this, CTCF knockdown reduced the formation of γ-radiation-induced Rad51 foci, as well as the recruitment of Rad51 to laser-irradiated sites of DNA lesions and to I-SceI-induced DSBs. We further show that CTCF is associated with DNA HR repair factors MDC1 and AGO2, and directly interacts with Rad51 via its C terminus. These analyses establish a direct, functional role of CTCF in DNA repair and provide a potential link between genome organization and genome stability. |
| Databáze: | OpenAIRE |
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