Targeted DNA methylation by homology-directed repair in mammalian cells. Transcription reshapes methylation on the repaired gene

Morano, Annalisa; Angrisano, Tiziana; Russo, G.; Landi, Rosaria; Pezone, Antonio; Bartollino, Silvia; Zuchegna, Candida; Babbio, Federica; Bonapace, Ian Marc; Allen, Brittany; Muller, Mark T.; Chiariotti, Lorenzo; Gottesman, Max E.; Porcellini, Antonio; Avvedimento, Enrico V.

doi:10.1093/nar/gkt920

Cited by 63 publications

(82 citation statements)

References 41 publications

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“…Although not yet fully understood, Gadd45a may provide a regulatory but also a recruitment function for such a complex as it physically and functional interacts with DNMT1,118,121,146].…”

Section: Discussionmentioning

confidence: 99%

“…So was TET1 found to counteract the spreading of DNA methylation into CGIs in human HEK293 cells [116] and TET-dependent 5hmC formation as well as a transient Gadd45a-modulated DNA hypermethylation was observed at sites of DNA repair [117,118]. These temporary changes of the DNA methylation at DNA repair sites appear to be re-shaped through an involvement of the transcriptional machinery [118].…”

Section: Maintenance Of Identity and Epigenetic Plasticity In Differementioning

confidence: 99%

“…Alternatively, recruitment as well as enzymatic activity of TETs was proposed to be regulated by 5mC-binding proteins such as members of the MBD family [143,144] or by PARP1 [145]. Moreover, targeting of the DNA demethylation machinery could be achieved via interactions of TDG with transcription factors and TET proteins as supported by the observation that TDG binding to a gene promoter is sufficient to reactivate gene expression [128].Although not yet fully understood, Gadd45a may provide a regulatory but also a recruitment function for such a complex as it physically and functional interacts with DNMT1,118,121,146].The scientific and technical progress of recent years facilitated the identification of DNA repair factors as key players of active DNA demethylation and provided some insight into their role in epigenetic regulation. Yet, we are far from understanding the true biology of these processes, i.e.…”

mentioning

confidence: 99%

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Active DNA demethylation by DNA repair: Facts and uncertainties

2016

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Pathways that control and modulate DNA methylation patterning in mammalian cells were poorly understood for a long time, although their importance in establishing and maintaining cell type-specific gene expression was well recognized. The discovery of proteins capable of converting 5-methylcytosine (5mC) to putative substrates for DNA repair introduced a novel and exciting conceptual framework for the investigation and ultimate discovery of molecular mechanisms of DNA demethylation. Against the prevailing notion that DNA methylation is a static epigenetic mark, it turned out to be dynamic and distinct mechanisms appear to have evolved to effect global and locus-specific DNA demethylation. There is compelling evidence that DNA repair, in particular base excision repair, contributes significantly to the turnover of 5mC in cells. By actively demethylating DNA, DNA repair supports the developmental establishment as well as the maintenance of DNA methylation landscapes and gene expression patterns. Yet, while the biochemical pathways are relatively well-established and reviewed, the biological context, function and regulation of DNA repair-mediated active DNA demethylation remains uncertain. In this review, we will thus summarize and critically discuss the evidence that associates active DNA demethylation by DNA repair with specific functional contexts including the DNA methylation erasure in the early embryo, the control of pluripotency and cellular differentiation, the maintenance of cell identity, and the nuclear reprogramming.

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“…Although not yet fully understood, Gadd45a may provide a regulatory but also a recruitment function for such a complex as it physically and functional interacts with DNMT1,118,121,146].…”

Section: Discussionmentioning

confidence: 99%

Section: Maintenance Of Identity and Epigenetic Plasticity In Differementioning

confidence: 99%

mentioning

confidence: 99%

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Active DNA demethylation by DNA repair: Facts and uncertainties

2016

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“…S3). To validate this finding in a different reporter model, we compared HDR efficiencies in wild type and knock down CCDC6 cells using a well established HeLa GFP reporter system (containing DR GFP, 25,[31][32][33][34] ). In this reporter, I-SceI expression was placed under control of a teton promoter.…”

Section: Ccdc6 Loss Inhibits Homology-directed Repair (Hdr)mentioning

confidence: 97%

New therapeutic perspectives in CCDC6 deficient lung cancer cells

Morra

Luise

Visconti

et al. 2014

Intl Journal of Cancer

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Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coildomain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p 0.02) and negatively correlated to the disease free survival (p 0.01) and the overall survival (p 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC.

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“…DNA methylation, in addition to having a well-defined role in altering gene transcription, has a potential role in DNA damage repair. The DNA methylation reaction is catalysed by DNA methyl transferase 1 (DNMT1), and mouse cells lacking DNMT1 are genetically unstable [98][99][100] . In human cells, global loss of DNA methylation results in genome instability 101 .…”

Section: Changes In Non-genomic Factorsmentioning

confidence: 99%

Genomic integrity and the ageing brain

2015

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DNA damage is correlated with and may drive the ageing process. Neurons in the brain are postmitotic and are excluded from many forms of DNA repair; therefore, neurons are vulnerable to various neurodegenerative diseases. The challenges facing the field are to understand how and when neuronal DNA damage accumulates, how this loss of genomic integrity might serve as a 'time keeper' of nerve cell ageing and why this process manifests itself as different diseases in different individuals.

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Targeted DNA methylation by homology-directed repair in mammalian cells. Transcription reshapes methylation on the repaired gene

Cited by 63 publications

References 41 publications

Active DNA demethylation by DNA repair: Facts and uncertainties

Active DNA demethylation by DNA repair: Facts and uncertainties

New therapeutic perspectives in CCDC6 deficient lung cancer cells

Genomic integrity and the ageing brain

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