5-Hydroxymethylcytosine Marks Sites of DNA Damage and Promotes Genome Stability

Kafer, Georgia R.; Li, Xuan; Horii, Takuro; Suetake, Isao; Tsuji, Shoji; Hatada, Izuho; Carlton, Peter M.

doi:10.1016/j.celrep.2016.01.035

Cited by 163 publications

(137 citation statements)

References 48 publications

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“…Increase in ␥-H2AX foci formation and activation of CHK2 and P53 have also been observed with TET1 catalytic domain, suggesting a TET1-mediated role in increased DNA damages or decreased DNA repair [35]. Moreover, TET2-mediated 5-hmC has recently been found to colocalize with ␥-H2AX and to participate to DNA damage foci [36]. Alternatively, increased level of 5-hmC residues might also indirectly affect cell cycle through expression of genes responsible for DNA replication, elongation or damage responses.…”

Section: Impact Of Tet2-induced 5-hmc On Cell Cyclementioning

confidence: 90%

TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

Mahfoudhi¹,

Talhaoui

Cabagnols

et al. 2016

DNA Repair

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Section: Impact Of Tet2-induced 5-hmc On Cell Cyclementioning

confidence: 90%

TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

Mahfoudhi¹,

Talhaoui

Cabagnols

et al. 2016

DNA Repair

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“…28 In addition, 5hmC was reported to accumulate at DNA damage foci induced by irradiation and colocalize with major DNA damage response proteins 53BP1 and gH2AX, indicating that the TET family members and 5hmC play essential roles in ensuring genome integrity. 29 Given that Tet2 loss causes decreased 5hmC whereas Aid loss induces accumulation of 5hmC ( Figure 1D), it is possible that Tet2 loss and Aid loss demonstrate a different effect on hematopoiesis through the unique and specific biological role of 5hmC independent of DNA demethylation.…”

Section: Discussionmentioning

confidence: 99%

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Kunimoto¹,

McKenney

Meydan

et al. 2017

Blood

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• Aid loss leads to altered differentiation, transcription, and methylation in specific genetic loci in hematopoietic stem/progenitor cells.• Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD in myeloid leukemogenesis.Recent studies have reported that activation-induced cytidine deaminase (AID) and teneleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of AID in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to Tet2 loss, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation. (Blood. 2017;129(13):1779-1790

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“…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%

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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5-Hydroxymethylcytosine Marks Sites of DNA Damage and Promotes Genome Stability

Cited by 163 publications

References 48 publications

TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Active DNA demethylation by DNA repair: Facts and uncertainties

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