CTCF regulates the human p53 gene through direct interaction with its natural antisense transcript, Wrap53

Saldaña-Meyer, Ricardo; González-Buendía, Edgar; Guerrero, Georgina; Narendra, Varun; Bonasio, Roberto; Recillas‐Targa, Félix; Reinberg, Danny

doi:10.1101/gad.236869.113

Cited by 194 publications

(222 citation statements)

References 37 publications

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“…A recent study reported that CTCF maintains p53 expression and promotes p53 function in the DNA damage response through epigenetic regulation and binding to the antisense transcript originated from the p53 locus (27), suggesting that the RNA-binding properties of CTCF may play a role in DNA damage repair. Here we found that recruitment of CTCF to sites of DNA damage did not depend on the RNAbinding domain of CTCF, and that RNase A did not disrupt the association of CTCF and other DDR proteins (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Lang

Zheng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.CTCF | chromatin | genome stability | DNA repair | homologous recombination

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Section: Discussionmentioning

confidence: 99%

“…The full-length CTCF molecule was divided into several sections, and RFP tags were added (26,27) (Fig. S3D).…”

Section: Ctcf Prevents Genomic Instabilitymentioning

confidence: 99%

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

Lang

Zheng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Additionally, CTCF has a more direct influence on transcription; 7-14% of CTCF sites are found within promoter proximal regions (4). Functionally, there is evidence that CTCF acts primarily as a transcriptional activator in these cases, and it is unclear that its transactivating capabilities are dependent on epigenetic processes (5)(6)(7)(8); when bound within exonic regions, it promotes polymerase II (Pol II) pausing (9), adding another level of transcriptional regulation to its repertoire.…”

mentioning

confidence: 99%

Genome-wide targeting of the epigenetic regulatory protein CTCF to gene promoters by the transcription factor TFII-I

Peña-Hernández

Marques

Hilmi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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CCCTC-binding factor (CTCF) is a key regulator of nuclear chromatin structure and gene regulation. The impact of CTCF on transcriptional output is highly varied, ranging from repression to transcriptional pausing and transactivation. The multifunctional nature of CTCF may be directed solely through remodeling chromatin architecture. However, another hypothesis is that the multifunctional nature of CTCF is mediated, in part, through differential association with protein partners having unique functions. Consistent with this hypothesis, our mass spectrometry analyses of CTCF interacting partners reveal a previously undefined association with the transcription factor general transcription factor II-I (TFII-I). Biochemical fractionation of CTCF indicates that a distinct CTCF complex incorporating TFII-I is assembled on DNA. Unexpectedly, we found that the interaction between CTCF and TFII-I is essential for directing CTCF to the promoter proximal regulatory regions of target genes across the genome, particularly at genes involved in metabolism. At genes coregulated by CTCF and TFII-I, we find knockdown of TFII-I results in diminished CTCF binding, lack of cyclin-dependent kinase 8 (CDK8) recruitment, and an attenuation of RNA polymerase II phosphorylation at serine 5. Phenotypically, knockdown of TFII-I alters the cellular response to metabolic stress. Our data indicate that TFII-I directs CTCF binding to target genes, and in turn the two proteins cooperate to recruit CDK8 and enhance transcription initiation.

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“…Recently, by using PAR-CLIP, Ricardo et al [117] reported CTCF can bind a variety of RNAs in vivo. Moreover, they found CTCF can regulate p53 expression via binding Wrap53 RNA, which is an antisense transcript originating from the p53 locus.…”

Section: Studying Epigenetic Modification-associated Rnasmentioning

confidence: 99%

CLIP: viewing the RNA world from an RNA-protein interactome perspective

Zhang

Xie²,

Xu³

et al. 2015

Sci. China Life Sci.

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The pervasive transcription of the genome creates many types of non-coding RNAs (ncRNAs). However, we know very little regarding the functions and the regulatory mechanisms of these ncRNAs. Exploring the interactions of RNA and RNA binding proteins (RBPs) is vital because it can allow us to truly understand how these ncRNAs behave in vivo. High-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP or CLIP-seq) and its variants have been successfully used as systemic techniques to study RBP binding sites. In this review, we will explain the major differences between the CLIP techniques, summarize successful applications of these techniques, discuss limitations of CLIP, present some suggested solutions and project their promising future roles in studying the RNA world. CLIP, CLASH, RPBs, ncRNAs, functional RNomics Citation:Zhang

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CTCF regulates the human p53 gene through direct interaction with its natural antisense transcript, Wrap53

Cited by 194 publications

References 37 publications

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

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

Genome-wide targeting of the epigenetic regulatory protein CTCF to gene promoters by the transcription factor TFII-I

CLIP: viewing the RNA world from an RNA-protein interactome perspective

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