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Vitamin C and Somatic Cell Reprogramming
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
The alkylated DNA repair protein AlkB homologues (ALKBHs) are another group of α-KGDDs that can influence somatic cell reprogramming and be targeted for enhanced activity by vitamin C. ALKBH1 is a histone dioxygenase that removes methyl groups from histone H2A to regulate gene expression [66,67]. ALKBH1 expression is higher in stem cells than differentiated cells and increases during iPSC reprogramming [68,69]. Moreover, ALKBH1 interacts directly with the core pluripotency factors Oct4, Sox2, and Nanog at overlapping sites on chromatin and influences the expression of miRNAs important for maintaining ESC self-renewal and pluripotency [67]. Other AlkB homologues are indirectly implicated in the regulation of somatic cell reprogramming. RNA methyltransferases generate m6A modifications in mRNA transcripts that can be removed by two RNA demethylases—the AlkB homologues known as the fat-mass and obesity-associated (FTO) gene and AlkB homolog 5 (ALKBH5) [70,71]. Increased m6A abundance promotes the reprogramming of MEFs to pluripotent stem cells; conversely, reduced m6A levels impede reprogramming [72]. Vitamin C has recently been shown to promote erasure of m6A during the differentiation of pig oocytes [73]; however, the role of vitamin C in regulating m6A levels via the modulation of FTO or ALKBH activity during reprogramming has not yet been investigated.
Physiology and Growth
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
ALKBH proteins, the homologs of E. coli AlkB dioxygenase, which constitute a direct, single-protein repair system, protecting cellular DNA and RNA against the cytotoxic and mutagenic activity of alkylating agents, were found to increase the survival of the phage MS2 after treatment with such alkylating agents as methyl methanesulfonate or chloroacetaldehyde, indicating efficient repair of 1meA/3meC lesions and etheno adducts in the phage RNA (Mielecki et al. 2012).
RNA N6-methyladenosine methylation and skin diseases
Published in Autoimmunity, 2023
Yaqin Yu, Shuang Lu, Hui Jin, Huan Zhu, Xingyu Wei, Tian Zhou, Ming Zhao
m6A erasers remove m6A modifications from RNA, also known as demethylases. The only two erasers identified to date are fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), which both belong to the Fe(ii) and α-ketoglutarate-dependent AlkB family. Early studies identified an important role for FTO in the regulation of energy homeostasis and obesity [28,29]. The demethylation function of FTO controls exon splicing of the adipogenic regulator RUNX1 partner transcriptional co-repressor 1 (RUNX1T1), thereby regulating adipogenesis [30]. FTO demethylates N1-methyladenosine (m1A) in tRNA as well as internal m6A, and cap N6, 2-O-dimethyladenosine (m6Am) in mRNA and snRNA [31]. The mechanism of FTO demethylation is to catalyse the oxidative demethylation of m6A to N6-hydroxymethyladenosine (hm6A), N6-formyladenosine (f6A) and A stepwise [32]. In contrast, ALKBH5 interacts with intranuclear RNA directly to remove the m6A modification without intermediate steps [33]. Further discussion about m6A erasers can be found in the subsequent sections.
Role of N6-methyladenosine modification in pathogenesis of ischemic stroke
Published in Expert Review of Molecular Diagnostics, 2022
Hongtao Chang, Jun Yang, Qianwen Wang, Jingjing Zhao, Ruixia Zhu
Erasers are responsible for removing RNA methylation-containing obesity-associated protein (FTO) and ALKB homolog 5 (ALKHB5). In 2007, Frayling et al [14]. discovered genetic variants of a gene related to obesity risk and the gene was officially named FTO. FTO is abundant in the brain, especially in neurons; thus, it may play a significant role in the brain. Jia et al [15]. reported that FTO effectively demethylates m6A in vitro and the intracellular m6A content is affected by the oxidative activity of FTO. Furthermore, FTO affects protein levels because of its function in mRNA translation, decay, and stability [15]. ALKBH5 is another m6A demethylase that is localized to the nucleus and Zheng et al [16]. found that the total m6A RNA level was decreased in ALKBH5 over-expressing cells. However, unlike FTO, ALKBH5 may remove methyl groups directly and regulate mRNA splicing [17].
Environmental exposures and RNA N6-Methyladenosine modified long Non-Coding RNAs
Published in Critical Reviews in Toxicology, 2020
m6A is the first modification which has been characterized with its three types of enzyme including writers, erasers, and readers. The writer catalyzes the addition of methyl group to the adenosine. Currently, several methyltransferase enzymes have been identified including METTL3 (methyltransferase like 3), METTL14 (methyltransferase like 14), METTL16 (methyltransferase like 16), RBM15 (RNA binding motif protein 15), WTAP (Wilm’s tumor 1-associating protein), and KIAA1429 (vir like m6A methyltransferase associated). The ‘reader’ proteins recognize and utilize the chemical marks in their function such as HNRNPC (heterogeneous nuclear ribonucleoprotein C), HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), YTHDF2 (YTH N6-Methyladenosine RNA binding protein 2), YTHDF1 (YTH N6-Methyladenosine RNA binding protein 1), and eIF3 (eukaryotic initiation factor 3). The eraser is an enzyme that catalyzes to remove the methyl group from the adenosine including FTO/ALKBH9 (alpha-ketoglutarate dependent dioxygenase) and ALKBH5 (alkb homolog 5, RNA demethylase) (Cao et al. 2016).