DNA repair and erasure of 5‐methylcytosine in vertebrates

Abstract

DNA methylation plays important roles in development and disease. Yet, only recently has the dynamic nature of this epigenetic mark via oxidation and DNA repair-mediated demethylation been recognized. A major conceptual challenge to the model that DNA methylation is reversible is the risk of genomic instability, which may come with widespread DNA repair activity. Here, we focus on recent advances in mechanisms of TET-TDG mediated demethylation and cellular strategies that avoid genomic instability. We highlight the recently discovered involvement of NEIL DNA glycosylases, which cooperate with TDG in oxidative demethylation to accelerate substrate turnover and promote the organized handover of harmful repair intermediates to maintain genome stability.

Tet Enzymes, Variants, and Differential Effects on Function

“…The three family members catalyze the hydroxylation of DNA methyl cytosine (5mC) into 5-hydroxymethylcytosine (5hmC), and can further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC). During active demethylation, these 5fC- and 5caC-modified cytosines are rapidly excised by thymine DNA glycosylase (TDG), after which they are replaced by unmodified cytosines through base excision repair (BER) mechanisms (Tahiliani et al, 2009 ; Ito et al, 2010 , 2011 ; He et al, 2011 ; Maiti and Drohat, 2011 ; Schomacher and Niehrs, 2017 ).…”

Making headway towards understanding how epigenetic mechanisms contribute to early-life effects

“…The TET family has three members, TET1, TET2 and TET3, which can catalyse conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5carboxylcytosine (5caC) through their oxidizing activity [15,16]. The oxidized groups (5fc and 5caC) are excised and replaced by unmodified cytosine via either thymine-DNA-glycosylase (TDG) catalysed base excision or DNA base excision repair (BER) [15,[17][18][19][20][21]. Therefore, this process is defined as active DNA demethylation that is independent of DNA replication.…”

Panorama epigenético del mesotelioma pleural maligno

“…40,41 Los grupos de dinucleótidos CpG están localizados en www.medigraphic.org.mx promotores de aproximadamente el 60% de los genes; la mayoría de estas islas no están metiladas, lo que permite una estructura relajada y transcripcional activa (eucromatina). [42][43][44][45] Durante la transformación maligna, la sobreexpresión o la orientación aberrante de los componentes de la maquinaria de metilación del ADN produce un silenciamiento epigenético de los genes relacionados con la diferenciación, muchos son supresores de tumores. 46,47 La desmetilación del ADN es pasiva durante la replicación del ADN.…”