Active DNA Demethylation Mediated by DNA Glycosylases

By Jian‐Kang Zhu. Annual Review of Genetics, 2009

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Active DNA demethylation is involved in many vital developmental and physiological processes of plants and animals. Recent genetic and biochemical studies in Arabidopsis have demonstrated that a subfamily of DNA glycosylases function to promote DNA demethylation through a base excision-repair pathway. These specialized bifunctional DNA glycosylases remove the 5-methylcytosine base and then cleave the DNA backbone at the abasic site, resulting in a gap that is then filled with an unmethylated cytosine nucleotide by as yet unknown DNA polymerase and ligase enzymes. Evidence suggests that active DNA demethylation in mammalian cells is also mediated at least in part by a base excision repair pathway where the AID/Apobec family of deaminases convert 5-methylcytosine to thymine followed by G/T mismatch repair by the DNA glycosylase MBD4 or TDG. This review also discusses other possible mechanisms of active DNA demethylation, how genome DNA methylation status might be sensed to regulate the expression of demethylase genes, and the targeting of demethylases by small RNAs.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/46702165586ebf7adb5801bf8c0989c5c1517b7e

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Citations in the corpus

Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “…that plants (e.g., Arabidopsis thaliana) use the Demeter (DME)/repressor of silencing 1 (ROS1) family of 5mC glycosylases and the base excision repair (BER) pathway to achieve active DNA demethylation (Zhu 2009), a mammalian ortholog of the DME/ROS1 family of glycosylases has yet to be identified.”
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, neutral): “, Arabidopsis thaliana), active erasure of 5mC is mediated by the Demeter (DME)/repressor of silencing 1 (ROS1) family of DNA glycosylases and base excision repair (BER) machinery (Zhu, 2009) (Figure 1C).”
DNA methylation: superior or subordinate in the epigenetic hierarchy? (2011, background): “DNA methylation is typically removed during zygote formation and then re-established in the embryo at approximately the time of implantation.(3) Most DNA methylation is essential for normal development, and it plays a very important role in a number of key processes including genomic imprinting, X-c”
Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain (2011, neutral): “In plants, a group of 5mC-specific DNA glycosylases, including ROS1, DME, and DML2/3, can specifically excise 5mC to initiate the base excision repair (BER) to achieve active DNA demethylation (Zhu, 2009).”
Epigenetic regulation of neurogenesis in the adult mammalian brain (2011, background): “residue of CpG dinucleotides to generate 5-methylcytosine on the pyrimidine ring (Jaenisch & Bird, 2003; Suzuki & Bird, 2008; Zhu, 2009).”
Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates (2010, background): “Whereas it is well established that mC is a crucial epigenetic marker [3], the function of the sixth base hmC is currently unknown, but it is speculated that it is involved in epigenetic regulation events or in active demethylation processes [4,5,6,7,8].”
Uncovering the role of 5-hydroxymethylcytosine in the epigenome (2011, background): “Is 5hmC a demethylation intermediate? Several mechanisms for the removal of 5mC have been propose”
Establishing, maintaining and modifying DNA methylation patterns in plants and animals (2010, background): “Active demethylation is achieved in plants by DNA glycosylase activity, probably in combination with the base excision repair (BER) pathwa”
Active DNA demethylation: many roads lead to Rome (2010, background): “Strong genetic and biochemical evidence supports the use of this mechanism in plant”