A CpG-rich RNA and an RNA helicase tightly associated with the DNA demethylation complex are present mainly in dividing chick embryo cells

Schwarz, Steffen; Bourgeois, Claire A.; Soussaline, F.; Homsy, Charles; Podestà, Adriano; Jost, Jean-Pierre

doi:10.1078/0171-9335-00070

Cited by 12 publications

(7 citation statements)

References 20 publications

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“…Along these lines, it was shown that the estrogen responsive pS2/TFF1 promoter undergoes cyclic DNA methylation and demethylation during transcriptional activation, involving 5-meC deamination by the methyltransferase Dnmt3a/b itself and subsequent TDG-dependent BER (Metivier et al 2008; Kangaspeska et al 2008). The demethylation complex also includes the RNA helicase p68, implicating an RNA component in either targeting and/or stabilization of the complex, consistent with previously reported observations on the chicken 5-methylcytosine DNA glycosylase (Jost et al 1997; Schwarz et al 2000). Additional support for a deamination-coupled demethylation pathway came from a study in zebrafish embryos, implicating AID in the deamination of 5-meC and MBD4 in the excision of the resulting G•T mismatch, as well as Gadd45 as an auxiliary factor (Rai et al 2008).…”

Section: Functions Of Dna Glycosylases Beyond Dna Repairsupporting

confidence: 89%

DNA glycosylases: in DNA repair and beyond

2011

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The base excision repair machinery protects DNA in cells from the damaging effects of oxidation, alkylation, and deamination; it is specialized to fix single-base damage in the form of small chemical modifications. Base modifications can be mutagenic and/or cytotoxic, depending on how they interfere with the template function of the DNA during replication and transcription. DNA glycosylases play a key role in the elimination of such DNA lesions; they recognize and excise damaged bases, thereby initiating a repair process that restores the regular DNA structure with high accuracy. All glycosylases share a common mode of action for damage recognition; they flip bases out of the DNA helix into a selective active site pocket, the architecture of which permits a sensitive detection of even minor base irregularities. Within the past few years, it has become clear that nature has exploited this ability to read the chemical structure of DNA bases for purposes other than canonical DNA repair. DNA glycosylases have been brought into context with molecular processes relating to innate and adaptive immunity as well as to the control of DNA methylation and epigenetic stability. Here, we summarize the key structural and mechanistic features of DNA glycosylases with a special focus on the mammalian enzymes, and then review the evidence for the newly emerging biological functions beyond the protection of genome integrity.

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Section: Functions Of Dna Glycosylases Beyond Dna Repairsupporting

confidence: 89%

DNA glycosylases: in DNA repair and beyond

2011

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“…This raises the possibility that Gadd45a RNPs are associated with genes undergoing active DNA demethylation and transcriptional activation. Of note, p68/Ddx5, which colocalizes with Gadd45a in nuclear speckles, was previously described as a component of a DNA demethylase complex [26], [27].…”

Section: Discussionmentioning

confidence: 88%

Gadd45a Is an RNA Binding Protein and Is Localized in Nuclear Speckles

et al. 2011

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BackgroundThe Gadd45 proteins play important roles in growth control, maintenance of genomic stability, DNA repair, and apoptosis. Recently, Gadd45 proteins have also been implicated in epigenetic gene regulation by promoting active DNA demethylation. Gadd45 proteins have sequence homology with the L7Ae/L30e/S12e RNA binding superfamily of ribosomal proteins, which raises the question if they may interact directly with nucleic acids.Principal FindingsHere we show that Gadd45a binds RNA but not single- or double stranded DNA or methylated DNA in vitro. Sucrose density gradient centrifugation experiments demonstrate that Gadd45a is present in high molecular weight particles, which are RNase sensitive. Gadd45a displays RNase-sensitive colocalization in nuclear speckles with the RNA helicase p68 and the RNA binding protein SC35. A K45A point mutation defective in RNA binding was still active in DNA demethylation. This suggests that RNA binding is not absolutely essential for demethylation of an artificial substrate. A point mutation at G39 impared RNA binding, nuclear speckle localization and DNA demethylation, emphasizing its relevance for Gadd45a function.SignificanceThe results implicate RNA in Gadd45a function and suggest that Gadd45a is associated with a ribonucleoprotein particle.

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“…Multiple DNA methylases and demethylases are reported (see review, Wolffe et al, 1999). The demethylation activities are remarkable and in some cases may require both RNA and proteins (Schwarz et al, 2000). Demethylation by MBD2/Demethylase has been described in detail, but not all groups have detected demethylation associated with this protein (Bhattacharya et al, 1999;Detich et al, 2002;Ng et al, 1999).…”

Section: Fig 4 Parental Origin Of Thementioning

confidence: 97%

Disruption of the genomic imprint in trans with homologous recombination at Snrpn in ES cells

Tsai

Bressler

Jiang

et al. 2003

Genesis

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In gene targeting studies of the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) domain in mouse ES cells, we recovered only recombinants with the paternal allele for constructs at exons 2 or 3 of the imprinted, maternally silenced Snurf-Snrpn gene. These sites lie close to the imprinting center (IC) for this domain. In contrast, recombinants for Ube3a within the same imprinted domain were recovered with equal frequency on the maternal and paternal alleles. In addition, gene targeting of the paternal allele for Snurf-Snrpn resulted in partial or complete demethylation in trans with activation of expression for the previously silenced maternal allele. The imprint switching of the maternal allele in trans is not readily explained by competition for trans-acting factors and adds to a growing body of evidence indicating homologous association of oppositely imprinted chromatin domains in somatic mammalian cells.

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A CpG-rich RNA and an RNA helicase tightly associated with the DNA demethylation complex are present mainly in dividing chick embryo cells

Cited by 12 publications

References 20 publications

DNA glycosylases: in DNA repair and beyond

DNA glycosylases: in DNA repair and beyond

Gadd45a Is an RNA Binding Protein and Is Localized in Nuclear Speckles

Disruption of the genomic imprint in trans with homologous recombination at Snrpn in ES cells

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