CTCF facilitates DNA double-strand break repair by enhancing homologous recombination repair

Hilmi, Khalid; Jangal, Maïka; Marques, Maud; Zhao, Tiejun; Saad, Amine; Zhang, Chenxi; Luo, Vincent; Syme, Alasdair; Rejon, Carlis; Yu, Zhenbao; Asiev, Krum; Fabian, Marc R.; Richard, Stéphane; Alaoui‐Jamali, Moulay A.; Orthwein, Alexandre; McCaffrey, Luke; Witcher, Michael

doi:10.1126/sciadv.1601898

Cited by 67 publications

(89 citation statements)

References 71 publications

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“…Abrogation of ERCC1 in Ercc1 −/− mice or exposure of primary embryonic fibroblasts to the DNA interstrand cross‐linker mitomycin triggers the localization of CTCF to heterochromatin and the dissociation of the CTCF–cohesin complex and ATRX from promoters and imprinted control regions. These findings are also in agreement with the newly identified role for CTCF in facilitating the repair of DNA DSBs through HR . CTCF also interacts with CSB .…”

Section: Ner Factors and Chromatin Looping: The Ctcf Linksupporting

confidence: 90%

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

et al. 2019

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Transcription is a potential threat to genome integrity, and transcription‐associated DNA damage must be repaired for proper messenger RNA (mRNA) synthesis and for cells to transmit their genome intact into progeny. For a wide range of structurally diverse DNA lesions, cells employ the highly conserved nucleotide excision repair (NER) pathway to restore their genome back to its native form. Recent evidence suggests that NER factors function, in addition to the canonical DNA repair mechanism, in processes that facilitate mRNA synthesis or shape the 3D chromatin architecture. Here, these findings are critically discussed and a working model that explains the puzzling clinical heterogeneity of NER syndromes highlighting the relevance of physiological, transcription‐associated DNA damage to mammalian development and disease is proposed.

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Section: Ner Factors and Chromatin Looping: The Ctcf Linksupporting

confidence: 90%

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

et al. 2019

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“…DSB sites were still predicted well (AUROC = 0.869 and AUPR = 0.792; Additional file 1: Figure S5a and S5b), and CTCF and H3K4me1 were the most highly predictive variables (Additional file 1: Figure S5c). This revealed enhancer looping as a major driver of DSBs, in agreement with recent studies showing that DSBs form at loop anchors [35] and that CTCF facilitates DSB repair [36]. These results demonstrate that DSBs can be accurately predicted at less than 1-kb resolution using just a small amount of data.…”

Section: Prediction Using Epigenomic and Chromatin Datasupporting

confidence: 89%

Predicting double-strand DNA breaks using epigenome marks or DNA at kilobase resolution

Mourad

Cuvier

2017

Preprint

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Double-strand breaks (DSBs) result from the attack of both DNA strands by multiple sources, including radiation and chemicals. DSBs can cause the abnormal chromosomal rearrangements associated with cancer. Recent techniques allow the genome-wide mapping of DSBs at high resolution, enabling the comprehensive study of their origins. However, these techniques are costly and challenging. Hence, we devise a computational approach to predict DSBs using the epigenomic and chromatin context, for which public data are readily available from the ENCODE project. We achieve excellent prediction accuracy at high resolution. We identify chromatin accessibility, activity, and long-range contacts as the best predictors.

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“…The chromosome architectural proteins CTCF and cohesin are recruited to sites of DNA damage 19 . CTCF occupancy increases both at binding sites flanking γ-H2AX domains 18 and at sites of DNA lesions 17 after DNA damage is induced. In addition to their role in the DNA damage response, CTCF and cohesin are known to be important for the formation of TADs, and alterations of CTCF and cohesin can lead to an overall change in local genome topology 34 .…”

Section: Tad Boundary Strength and Ctcf Loops Increase After Exposurementioning

confidence: 99%

“…This suggests that changes in the structure of local genome domains may happen at a broader scale after IR. Additionally, CCCTC-binding factor (CTCF) and cohesin have been shown to be early responders to DNA damage induced by IR 17,18,19,20 . These proteins have also been recently demonstrated to play significant roles in chromosome folding 21,22,23,24 , contributing to the formation of topologically associating domains (TADs).…”

mentioning

confidence: 99%

Radiation-Induced DNA Damage and Repair Effects on 3D Genome Organization

Sanders

Freeman

et al. 2019

Preprint

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The three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. Fibroblasts, lymphoblasts, and ATM-deficient fibroblasts were irradiated with 5 Gy X-rays and Hi-C was performed after 30 minutes, 24 hours, or 5 days after irradiation. 3D genome changes after irradiation were cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repairproficient cell types exhibited an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation was not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.2 Translocations, deletions, and other genomic aberrations that may follow DNA damage can lead to cancer by directly mutating genes or altering their regulation 7, 8 . Recently, it has become clear that the disruption of 3D genome domains can also be oncogenic 9 . Does the process of DNA repair protect the 3D folding of the genome as well as the linear DNA sequence? Certain cell types are considered to be more radiosensitive than others, but little is known about what contributes to their radiosensitivity. The possibility remains that cell type specific chromosome positioning, along with initial epigenetic chromatin and folding states can influence which translocations occur and how well DNA is able to repair after exposure to IR, helping to explain why certain cell types are more sensitive to radiation 8, 10, 11. Previous studies suggest that DNA repair efficiency may differ for heterochromatin and euchromatin 12,13 . Heterochromatic regions may be more mobile and move to DNA repair sites, where they decondense 14,15 . Condensation or decondensation of specific chromatin regions may not be determined by their preexisting histone modifications 14 , suggesting that other factors may contribute to changes in 3D genome structure after DNA damage. One previous study demonstrated spatial clustering of DSBs in active genes by inducing specific breaks and measuring their interactions with Capture Hi-C 16 . This suggests that changes in the structure of local genome domains may happen at a broader scale after IR. Additionally, CCCTC-binding factor (CTCF) and cohesin have been shown to be early responders to DNA damage induced by IR 17,18,19,20 . These proteins have also been recently demonstrated to play significant roles in chromosome folding 21,22,23,24 , contributing to the formation of topologically associating domains (TADs). These genomic domains intera...

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CTCF facilitates DNA double-strand break repair by enhancing homologous recombination repair

Abstract: A new role for the mutlifunctional protein CTCF in the repair of DNA double-strand breaks is discovered.

Cited by 67 publications

References 71 publications

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

Predicting double-strand DNA breaks using epigenome marks or DNA at kilobase resolution

Radiation-Induced DNA Damage and Repair Effects on 3D Genome Organization

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