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Fange Liu, Wesley Clark, Guanzheng Luo, Xiaoyun Wang, Ye Fu, Jiangbo Wei, Xiao Wang, Ziyang Hao, Qing Dai, Guanqun Zheng, Honghui Ma, Dali Han, Molly Evans, Arne Klungland, Tao Pan, Chuan He
No abstract text is available yet for this article.
December 15, 2016: Cell
Chenchen Zhou, Yuting Liu, Xiaobing Li, Jing Zou, Shujuan Zou
ALKBH1 was recently discovered as a demethylase for DNA N(6)-methyladenine (N6-mA), a new epigenetic modification, and interacts with the core transcriptional pluripotency network of embryonic stem cells. However, the role of ALKBH1 and DNA N6-mA in regulating osteogenic differentiation is largely unknown. In this study, we demonstrated that the expression of ALKBH1 in human mesenchymal stem cells (MSCs) was upregulated during osteogenic induction. Knockdown of ALKBH1 increased the genomic DNA N6-mA levels and significantly reduced the expression of osteogenic-related genes, alkaline phosphatase activity, and mineralization...
2016: Bone Research
Fange Liu, Wesley Clark, Guanzheng Luo, Xiaoyun Wang, Ye Fu, Jiangbo Wei, Xiao Wang, Ziyang Hao, Qing Dai, Guanqun Zheng, Honghui Ma, Dali Han, Molly Evans, Arne Klungland, Tao Pan, Chuan He
tRNA is a central component of protein synthesis and the cell signaling network. One salient feature of tRNA is its heavily modified status, which can critically impact its function. Here, we show that mammalian ALKBH1 is a tRNA demethylase. It mediates the demethylation of N(1)-methyladenosine (m(1)A) in tRNAs. The ALKBH1-catalyzed demethylation of the target tRNAs results in attenuated translation initiation and decreased usage of tRNAs in protein synthesis. This process is dynamic and responds to glucose availability to affect translation...
October 20, 2016: Cell
Natalie P Archer, Virginia Perez-Andreu, Michael E Scheurer, Karen R Rabin, Erin C Peckham-Gregory, Sharon E Plon, Ryan C Zabriskie, Pedro A De Alarcon, Karen S Fernandez, Cesar R Najera, Jun J Yang, Federico Antillon-Klussmann, Philip J Lupo
BACKGROUND: Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility...
December 1, 2016: Cancer
Sara Haag, Katherine E Sloan, Namit Ranjan, Ahmed S Warda, Jens Kretschmer, Charlotte Blessing, Benedikt Hübner, Jan Seikowski, Sven Dennerlein, Peter Rehling, Marina V Rodnina, Claudia Höbartner, Markus T Bohnsack
Mitochondrial gene expression uses a non-universal genetic code in mammals. Besides reading the conventional AUG codon, mitochondrial (mt-)tRNA(M)(et) mediates incorporation of methionine on AUA and AUU codons during translation initiation and on AUA codons during elongation. We show that the RNA methyltransferase NSUN3 localises to mitochondria and interacts with mt-tRNA(M)(et) to methylate cytosine 34 (C34) at the wobble position. NSUN3 specifically recognises the anticodon stem loop (ASL) of the tRNA, explaining why a mutation that compromises ASL basepairing leads to disease...
October 4, 2016: EMBO Journal
Endalkachew A Alemu, Chuan He, Arne Klungland
The AlkB gene that protects E.coli against methylation damage to DNA was identified more than 3 decades ago. 20 years later, the AlkB protein was shown to catalyze repair of methylated DNA base lesions by oxidative demethylation. Two human AlkB homologs were characterized with similar DNA repair activities and seven additional human AlkB homologs were identified based on sequence homology. All these dioxygenases, ALKBH1-8 and FTO, contain a conserved α-ketoglutarate/iron-dependent domain for methyl modifications and de-modifications...
August 2016: DNA Repair
Tao P Wu, Tao Wang, Matthew G Seetin, Yongquan Lai, Shijia Zhu, Kaixuan Lin, Yifei Liu, Stephanie D Byrum, Samuel G Mackintosh, Mei Zhong, Alan Tackett, Guilin Wang, Lawrence S Hon, Gang Fang, James A Swenberg, Andrew Z Xiao
It has been widely accepted that 5-methylcytosine is the only form of DNA methylation in mammalian genomes. Here we identify N(6)-methyladenine as another form of DNA modification in mouse embryonic stem cells. Alkbh1 encodes a demethylase for N(6)-methyladenine. An increase of N(6)-methyladenine levels in Alkbh1-deficient cells leads to transcriptional silencing. N(6)-methyladenine deposition is inversely correlated with the evolutionary age of LINE-1 transposons; its deposition is strongly enriched at young (<1...
April 21, 2016: Nature
Rune Ougland, Ida Jonson, Marivi Nabong Moen, Gaute Nesse, Gry Asker, Arne Klungland, Elisabeth Larsen
BACKGROUND/AIMS: ALKBH1, an AlkB homologue in the 2-oxoglutarate and Fe2+ dependent hydroxylase family, is a histone dioxygenase that removes methyl groups from histone H2A. Studies of transgenic mice lacking Alkbh1 reveal that most Alkbh1-/- embryos die during embryonic development. Embryonic stem cells (ESCs) derived from these mice have prolonged expression of pluripotency markers and delayed induction of genes involved in neural differentiation, indicating that ALKBH1 is involved in regulation of pluripotency and differentiation...
2016: Cellular Physiology and Biochemistry
Bogdan I Fedeles, Vipender Singh, James C Delaney, Deyu Li, John M Essigmann
The AlkB family of Fe(II)- and α-ketoglutarate-dependent dioxygenases is a class of ubiquitous direct reversal DNA repair enzymes that remove alkyl adducts from nucleobases by oxidative dealkylation. The prototypical and homonymous family member is an Escherichia coli "adaptive response" protein that protects the bacterial genome against alkylation damage. AlkB has a wide variety of substrates, including monoalkyl and exocyclic bridged adducts. Nine mammalian AlkB homologs exist (ALKBH1-8, FTO), but only a subset functions as DNA/RNA repair enzymes...
August 21, 2015: Journal of Biological Chemistry
Rune Ougland, Torbjørn Rognes, Arne Klungland, Elisabeth Larsen
The DNA repair enzyme AlkB was identified in E. coli more than three decades ago. Since then, nine mammalian homologs, all members of the superfamily of alpha-ketoglutarate and Fe(II)-dependent dioxygenases, have been identified (designated ALKBH1-8 and FTO). While E. coli AlkB serves as a DNA repair enzyme, only two mammalian homologs have been confirmed to repair DNA in vivo. The other mammalian homologs have remarkably diverse substrate specificities and biological functions. Substrates recognized by the different AlkB homologs comprise erroneous methyl- and etheno adducts in DNA, unique wobble uridine modifications in certain tRNAs, methylated adenines in mRNA, and methylated lysines on proteins...
December 2015: Journal of Molecular Cell Biology
Pavel Silvestrov, Tina A Müller, Kristen N Clark, Robert P Hausinger, G Andrés Cisneros
The ability to repair DNA is important for the conservation of genetic information of living organisms. Cells have a number of ways to restore damaged DNA, such as direct DNA repair, base excision repair, and nucleotide excision repair. One of the proteins that can perform direct repair of DNA bases is Escherichia coli AlkB. In humans, there are 9 identified AlkB homologs, including AlkB homolog 1 (ALKBH1). Many of these proteins catalyze the direct oxidative dealkylation of DNA and RNA bases and, as such, have an important role in repairing DNA from damage induced by alkylating agents...
November 2014: Journal of Molecular Graphics & Modelling
Daria Zdżalik, Cathrine B Vågbø, Finn Kirpekar, Erna Davydova, Alicja Puścian, Agnieszka M Maciejewska, Hans E Krokan, Arne Klungland, Barbara Tudek, Erwin van den Born, Pål Ø Falnes
The ALKBH family of Fe(II) and 2-oxoglutarate dependent oxygenases comprises enzymes that display sequence homology to AlkB from E. coli, a DNA repair enzyme that uses an oxidative mechanism to dealkylate methyl and etheno adducts on the nucleobases. Humans have nine different ALKBH proteins, ALKBH1-8 and FTO. Mammalian and plant ALKBH8 are tRNA hydroxylases targeting 5-methoxycarbonylmethyl-modified uridine (mcm5U) at the wobble position of tRNAGly(UCC). In contrast, the genomes of some bacteria encode a protein with strong sequence homology to ALKBH8, and robust DNA repair activity was previously demonstrated for one such protein...
2014: PloS One
Tina A Müller, Kefei Yu, Robert P Hausinger, Katheryn Meek
Potential roles of the abasic site lyase activity associated with AlkB homolog 1 (ALKBH1) were assessed by studies focusing on the two cellular processes that create abasic sites as intermediates: base excision repair and class switch recombination. Alkbh1(-/-) pups (lacking exon 3) were born at a lower than expected frequency from heterozygous parents, suggesting a reduced survival rate and non-Mendelian inheritance, and they exhibited a gender bias in favor of males (70% males and 30% females). To study ALKBH1's potential involvement in DNA repair, fibroblasts were isolated from Alkbh1(-/-) mice, spontaneously immortalized and tested for resistance to DNA damaging agents...
2013: PloS One
Tina A Müller, Megan M Andrzejak, Robert P Hausinger
ALKBH1 (AlkB homologue 1) is a mammalian AlkB (2-oxoglutarate-dependent dioxygenase) homologue that possesses AP (abasic or apurinic/apyrimidinic) lyase activity. The AP lyase reaction is catalysed by imine formation with an active site lysine residue, and a covalent intermediate can be trapped in the presence of NaBH4. Surprisingly, ALKBH1 also forms a stable protein-DNA adduct in the absence of a reducing agent. Experiments with different substrates demonstrated that the protein covalently binds to the 5' DNA product, i...
June 15, 2013: Biochemical Journal
Anja Solberg, Adam B Robertson, Jan Magnus Aronsen, Oivind Rognmo, Ivar Sjaastad, Ulrik Wisløff, Arne Klungland
Mammals have nine homologues of the Escherichia coli AlkB repair protein: Alkbh1-8, and the fat mass and obesity associated protein FTO. In this report, we describe the first functional characterization of mouse Alkbh7. We show that the Alkbh7 protein is located in the mitochondrial matrix and that an Alkbh7 deletion dramatically increases body weight and body fat. Our data indicate that Alkbh7, directly or indirectly, facilitates the utilization of short-chain fatty acids, which we propose is the likely cause for the obesity phenotype observed in the Alkbh7(-/-) mice...
June 2013: Journal of Molecular Cell Biology
Linn G Bjørnstad, Trine J Meza, Marit Otterlei, Solveig M Olafsrud, Leonardo A Meza-Zepeda, Pål Ø Falnes
The Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenase AlkB from E. coli is a demethylase which repairs alkyl lesions in DNA, as well as RNA, through a direct reversal mechanism. Humans possess nine AlkB homologs (ALKBH1-8 and FTO). ALKBH2 and ALKBH3 display demethylase activities corresponding to that of AlkB, and both ALKBH8 and FTO are RNA modification enzymes. The biochemical functions of the rest of the homologs are still unknown. To increase our knowledge on the functions of ALKBH4 and ALKBH7 we have here performed yeast two-hybrid screens to identify interaction partners of the two proteins...
2012: PloS One
Line M Nordstrand, Kari Furu, Jonas Paulsen, Torbjørn Rognes, Arne Klungland
Piwi proteins and Piwi-interacting small RNAs (piRNAs) have known functions in transposon silencing in the male germline of fetal and newborn mice. Both are also present in adult testes; however, their function here remains a mystery. Here, we confirm that most piRNAs in meiotic spermatocytes originate from clusters in non-repeat intergenic regions of DNA. The regulation of these piRNA clusters, including the processing of the precursor transcripts into individual piRNAs, is accomplished through mostly unknown processes...
November 2012: Nucleic Acids Research
Rune Ougland, David Lando, Ida Jonson, John A Dahl, Marivi Nabong Moen, Line M Nordstrand, Torbjørn Rognes, Jeannie T Lee, Arne Klungland, Tony Kouzarides, Elisabeth Larsen
AlkB homolog 1 (ALKBH1) is one of nine members of the family of mammalian AlkB homologs. Most Alkbh1(-/-) mice die during embryonic development, and survivors are characterized by defects in tissues originating from the ectodermal lineage. In this study, we show that deletion of Alkbh1 prolonged the expression of pluripotency markers in embryonic stem cells and delayed the induction of genes involved in early differentiation. In vitro differentiation to neural progenitor cells (NPCs) displayed an increased rate of apoptosis in the Alkbh1(-/-) NPCs when compared with wild-type cells...
December 2012: Stem Cells
Lingmin Hu, Chen Wu, Xueying Zhao, Rebecca Heist, Li Su, Yang Zhao, Baohui Han, Songyu Cao, Minjie Chu, Juncheng Dai, Jing Dong, Yongqian Shu, Lin Xu, Yijiang Chen, Yi Wang, Feng Lu, Yue Jiang, Dianke Yu, Hongyan Chen, Wen Tan, Hongxia Ma, Jiaping Chen, Guangfu Jin, Tangchun Wu, Daru Lu, David C Christiani, Dongxin Lin, Zhibin Hu, Hongbing Shen
PURPOSE: Genetic variation may influence chemotherapy response and overall survival in cancer patients. EXPERIMENTAL DESIGN: We conducted a genome-wide scan in 535 advanced-stage non-small cell lung cancer (NSCLC) patients from two independent cohorts (307 from Nanjing and 228 from Beijing). A replication was carried out on an independent cohort of 340 patients from Southeastern China followed by a second validation on 409 patients from the Massachusetts General Hospital (Boston, MA)...
October 1, 2012: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Damian Mielecki, Dorota Ł Zugaj, Anna Muszewska, Jan Piwowarski, Aleksandra Chojnacka, Marcin Mielecki, Jadwiga Nieminuszczy, Marcin Grynberg, Elżbieta Grzesiuk
BACKGROUND: ALKBH proteins, the homologs of Escherichia coli AlkB dioxygenase, constitute a direct, single-protein repair system, protecting cellular DNA and RNA against the cytotoxic and mutagenic activity of alkylating agents, chemicals significantly contributing to tumor formation and used in cancer therapy. In silico analysis and in vivo studies have shown the existence of AlkB homologs in almost all organisms. Nine AlkB homologs (ALKBH1-8 and FTO) have been identified in humans. High ALKBH levels have been found to encourage tumor development, questioning the use of alkylating agents in chemotherapy...
2012: PloS One
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