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Rots M.G.,University of Groningen | Petersen-Mahrt S.K.,DNA Editing in Immunity and Epigenetics
Epigenomics | Year: 2013

Headline-grabbing attention has been given to DNA demethylation pathways as new epigenetic mechanisms, with reviews and hypotheses outnumbering research papers. As candidate proteins for DNA demethylation include well-known DNA repair enzymes, it was timely to join epigenetics and DNA repair experts at the first international meeting on DNA Demethylation, Repair and Beyond. New mechanistic insights were presented for known players orchestrating the symphony on cytosine - 'the symphony on C' (TET1, 2, 3; GADD45; AID; and TDG), while new instruments and classical themes were pulled into the amalgamation. What may appear as just an unintentional cacophony of random oxidative lesions and abasic sites in a bed of chromatin noise may turn out to be a gene-expressing regulatory melody. © 2013 Future Medicine Ltd. Source

Schmitz K.-M.,DNA Editing in Immunity and Epigenetics | Petersen-Mahrt S.K.,DNA Editing in Immunity and Epigenetics
Seminars in Immunology | Year: 2012

Activation induced deaminase (AID) has evolved with the immune system to enhance the ability of antibodies to bind and eliminate pathogens. It is a member of the AID/APOBEC family of proteins, which deaminate cytosine (or 5-methyl cytosine) in DNA leading to uracil (thymidine). These base modifications can lead to repair, DNA demethylation, mutagenesis, recombination, or viral/foreign DNA elimination. Because of their physiological function, their ubiquitous expression, and hormonal regulation (e.g. estrogen), these proteins play an important role in oncogenesis, with AID being directly implicated in B cell lymphomas. The targeting preference of each DNA deaminase provides a means to identify their mutation foot-print in tumours, and have implicated them in mutating the genome, including the loci of tumour suppressors, of various cancers (e.g. breast). In this special issue devoted to understanding AID function and regulation, leading members of the field discuss all aspects from AID transcriptional regulation, mRNA turnover, protein expression, modification, and transport, to complex formation, targeting and enzymatic turnover. AID's function will be discussed in context of DNA repair and how changes of key components of each pathway have an influence on the overall efficacy of targeted DNA deamination. © 2012 Elsevier Ltd. Source

Rangam G.,DNA Editing in Immunity and Epigenetics | Rangam G.,London Research Institute | Schmitz K.-M.,DNA Editing in Immunity and Epigenetics | Cobb A.J.A.,University of Reading | And 2 more authors.
PLoS ONE | Year: 2012

Activation induced deaminase (AID) deaminates cytosine to uracil, which is required for a functional humoral immune system. Previous work demonstrated, that AID also deaminates 5-methylcytosine (5 mC). Recently, a novel vertebrate modification (5-hydroxymethylcytosine - 5 hmC) has been implicated in functioning in epigenetic reprogramming, yet no molecular pathway explaining the removal of 5 hmC has been identified. AID has been suggested to deaminate 5 hmC, with the 5 hmU product being repaired by base excision repair pathways back to cytosine. Here we demonstrate that AID's enzymatic activity is inversely proportional to the electron cloud size of C5-cytosine - H > F > methyl >> hydroxymethyl. This makes AID an unlikely candidate to be part of 5 hmC removal. © 2012 Rangam et al. Source

Franchini D.-M.,DNA Editing in Immunity and Epigenetics | Schmitz K.-M.,DNA Editing in Immunity and Epigenetics | Petersen-Mahrt S.K.,DNA Editing in Immunity and Epigenetics
Annual Review of Genetics | Year: 2012

Demethylation of 5-methylcytosine in DNA is integral to the maintenance of an intact epigenome. The balance between the presence or absence of 5-methylcytosine determines many physiological aspects of cell metabolism, with a turnover that can be measured in minutes to years. Biochemically, addition of the methyl group is shared among all living kingdoms and has been well characterized, whereas the removal or reversion of this mark seems diverse and much less understood. Here, we present a summary of how DNA demethylation can be initiated directly, utilizing the ten-eleven translocation (TET) family of proteins, activation-induced deaminase (AID), or other DNA modifying enzymes, or indirectly, via transcription, RNA metabolism, or DNA repair; how intermediates in those pathways are substrates of the DNA repair machinery; and how demethylation pathways are linked and possibly balanced, avoiding mutations. © 2012 by Annual Reviews. Source

Incorvaia E.,DNA Editing in Immunity and Epigenetics | Sicouri L.,DNA Editing in Immunity and Epigenetics | Petersen-Mahrt S.K.,DNA Editing in Immunity and Epigenetics | Schmitz K.-M.,DNA Editing in Immunity and Epigenetics
Autoimmunity | Year: 2013

The human immune system is a complex dynamic network of soluble factors and specialized cells that can and need to act in an instance or keep a lifelong protection, with the consequence that health has to be maintained through genetic and environmental stimuli. Autoimmunity is a multifactorial disease, where this combination of genetic predisposition and environmental factors lead to disease etiology. As some autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) or other B cell autoimmunities have a very strong female gender bias, hormones, especially estrogen, have been implicated as environmental factors in driving the disease. One of the key regulators of B cell development is activation-induced deaminase (AID), as its molecular mechanism of cytosine deamination induces immunoglobulin affinity maturation and antibody class switching. In this review we will highlight some of the recent findings of how estrogen directly and indirectly activates AID expression, which in turn can lead to immune hyper-stimulation. Those regulatory pathways can be direct when the estrogen receptor (ER) binds the AID promoter, or indirect via activation of transcription factors that enhance AID expression (e.g., HoxC4). Estrogen's influence on AID will also be discussed in terms of microRNA processing for miRNA-155 and miRNA-181b. Important other external stimuli, such as EBV virus, in conjunction with estrogen can add another layer of regulation during autoimmune disease progression. Understanding these pathways will become more important as AID has now been implicated to play an important role in immune tolerance and actual elimination of autoantibodies. © Informa UK, Ltd. Source

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