GADD45a physically and functionally interacts with TET1

Kienhöfer, Sabine; Musheev, Michael U.; Stapf, Ulrike; Helm, Mark; Schomacher, Lars; Niehrs, Christof; Schäfer, Andrea

doi:10.1016/j.diff.2015.10.003

Cited by 38 publications

(45 citation statements)

References 50 publications

(89 reference statements)

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“…Consistently, TET1 and TDG were found to interact physically [27,98] and to be coordinated or targeted to chromatin by accessory factors such as Gadd45a (Fig. 2) [99,100]. A possible function of TET-TDG-mediated active DNA demethylation in ESCs could be to stabilize the expression of pluripotency genes and to maintain a transcriptionally poised state of lineage-specific genes, i.e.…”

Section: Control Of Pluripotency and Cellular Differentiationmentioning

confidence: 73%

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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Section: Control Of Pluripotency and Cellular Differentiationmentioning

confidence: 73%

Active DNA demethylation by DNA repair: Facts and uncertainties

2016

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“…GADD45A physically interacts with TET1 or TDG and seems to promote TET1 activity, and enhances removal of 5fC and 5caC by TDG 14,16,17 . GADD45A also recruits repair enzymes such as the 3′-NER endonuclease XPG to genomic sites DNA 41,42 .…”

Section: Discussionmentioning

confidence: 99%

“…Because GADD45A promotes TET1 activity and/or could recruit key player(s) of DNA repair 14,15,16,17 , we sought to augment Casilio-ME by constructing an upgraded version Casilio-ME2 which simultaneously recruits TET1(CD) and GADD45A to bridge 5mC oxidation with DNA repair at a specific genomic locus.…”

Section: Casilio-me2: Co-delivery Of Tet1(cd) and Gadd45a Enhances Gementioning

confidence: 99%

“…TDG acts on 5fC and 5caC and NEIL1 and NEIL2 DNA glycosylase/AP-lyase activities facilitate restoration of unmethylated cytosine by displacing TDG from the AP site to create a single strand DNA break substrate for further BER processing 6, 7, 8, 9, 10, 11, 12 . Interestingly, DNA demethylation is enhanced by GADD45A (Growth Arrest and DNA-Damage-inducible Alpha), a multi-faceted nuclear protein involved in maintenance of genomic stability, DNA repair and suppression of cell growth 13,14,15 . GADD45A interacts with TET1 and TDG, and was suggested to play a role in coupling 5mC oxidation to DNA repair 16,17 .…”

Section: Introductionmentioning

confidence: 99%

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Casilio-ME: Enhanced CRISPR-based DNA demethylation by RNA-guided coupling methylcytosine oxidation and DNA repair pathways

Taghbalout

Jillette

et al. 2019

Preprint

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We have developed a methylation editing toolbox, Casilio-ME, that enables not only RNA-guided methylcytosine editing by targeting TET1 to genomic sites, but also by codelivering TET1 and protein factors that couple methylcytosine oxidation to DNA repair activities, and/or promote TET1 to achieve enhanced activation of methylation-silenced genes. Delivery of TET1 activity by Casilio-ME1 robustly altered the CpG methylation landscape of promoter regions and activated methylation-silenced genes. We augmented Casilio-ME1 to simultaneously deliver the TET1-catalytic domain and GADD45A (Casilio-ME2) or NEIL2 (Casilio-ME3) to streamline removal of oxidized cytosine intermediates to enhance activation of targeted genes. Using two-in-one effectors or modular effectors, Casilio-ME2 and Casilio-ME3 remarkably boosted gene activation and methylcytosine demethylation of targeted loci. We expanded the toolbox to enable a stable and expression-inducible system for broader application of the Casilio-ME platforms. This work establishes an advanced platform for editing DNA methylation to enable transformative research investigations interrogating DNA methylomes.

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“…172 Recent studies find that Gadd45a interacts with and enhances the activity of TET enzymes and TDG. 173,174 …”

Section: Ber Mediates Active Dna Demethylation Vertebratesmentioning

confidence: 99%

Role of Base Excision “Repair” Enzymes in Erasing Epigenetic Marks from DNA

Drohat

Coey

2016

Chem. Rev.

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Base excision repair (BER) is one of several DNA repair pathways found in all three domains of life. BER counters the mutagenic and cytotoxic effects of damage that occurs continuously to the nitrogenous bases in DNA, and its critical role in maintaining genomic integrity is well established. However, BER also performs essential functions in processes other than DNA repair, where it acts on naturally modified bases in DNA. A prominent example is the central role of BER in mediating active DNA demethylation, a multi-step process that erases the epigenetic mark, 5-methylcytosine (5mC), or derivatives thereof, converting them back to cytosine. Here, we review recent advances in the understanding of how BER mediates this critical component of epigenetic regulation, in plants and animals.

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GADD45a physically and functionally interacts with TET1

Cited by 38 publications

References 50 publications

Active DNA demethylation by DNA repair: Facts and uncertainties

Active DNA demethylation by DNA repair: Facts and uncertainties

Casilio-ME: Enhanced CRISPR-based DNA demethylation by RNA-guided coupling methylcytosine oxidation and DNA repair pathways

Role of Base Excision “Repair” Enzymes in Erasing Epigenetic Marks from DNA

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