CTCF prevents genomic instability by promoting homologous recombination-directed DNA double-strand break repair

Lang, Fengchao; Li, Xin; Zheng, Wenhai; Li, Zhuoran; Lu, Dan; Chen, Guijun; Gong, Daohua; Yang, Liping; Fu, J.; Shi, Peng; Zhou, Jumin

doi:10.1073/pnas.1704076114

Cited by 72 publications

(76 citation statements)

References 41 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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“…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).…”

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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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“…TADs also function as structural domains to constrain long‐range contacts between enhancers and promoters such that they occur almost exclusively within TADs . Given the inextricable link between structure and function within the context of the cell nucleus, it is important to consider the role of HCO in maintaining genomic stability and fidelity and the resulting disruptions that occur in these TAD microenvironments introduced by translocations, deletions, inversions, and mutations during cancer progression (Figure ) …”

Section: Hco Is Integral To Fidelity Of Genome Regulationmentioning

confidence: 99%

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer

Fritz

Gillis

Gerrard

et al. 2019

Genes Chromosomes & Cancer

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Cells establish and sustain structural and functional integrity of the genome to support cellular identity and prevent malignant transformation. In this review, we present a strategic overview of epigenetic regulatory mechanisms including histone modifications and higher order chromatin organization (HCO) that are perturbed in breast cancer onset and progression. Implications for dysfunctions that occur in hormone regulation, cell cycle control, and mitotic bookmarking in breast cancer are considered, with an emphasis on epithelial‐to‐mesenchymal transition and cancer stem cell activities. The architectural organization of regulatory machinery is addressed within the contexts of translating cancer‐compromised genomic organization to advances in breast cancer risk assessment, diagnosis, prognosis, and identification of novel therapeutic targets with high specificity and minimal off target effects.

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CTCF prevents genomic instability by promoting homologous recombination-directed DNA double-strand break repair

Cited by 72 publications

References 41 publications

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

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

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer

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