New Articles in Cell Sub-Journal of East China Normal University

Researchers from East China Normal University confirmed that ABH2 participates in maintaining the integrity and transcription of ribosomal DNA (Ribosomal DNA, rDNA) by virtue of its DNA alkylation repair activity. The research paper was published in the "Cell Reports" magazine on August 22. The corresponding author of the article is Professor Jiemin Wong of the Institute of Life Medicine of East China Normal University. He has long been engaged in the research on the molecular mechanism of nuclear hormone receptor regulation of gene expression and the epigenetic molecular mechanism. His leading laboratory studies the nuclear Hormone receptor co-regulatory factor has obtained many breakthrough results, and has published nearly 70 papers in international core journals such as Cell, Nature and Science.

Genomic DNA is constantly being attacked by endogenous and environmental DNA-damaging substances, such as alkylating agents often leading to mutations or covalent modifications with genotoxicity. Studies have confirmed that a variety of mechanisms are involved in repairing these cytotoxic and / or mutational damages, including DNA glycosylase initiated base excision repair (BER). DNA glycosylase is a self-destructive methyltransferase, which can transfer methyl groups from DNA to the enzyme itself, and control the oxidative demethylation through ABH / ALKBH family proteins. The direct reversal of alkylation damage by oxidative demethylation was first reported in E. coli AlkB protein. In humans, there are 9 homologues of AlkB: ABH1–ABH8 and FTO. ABH2 and ABH3 have similar demethylase activity to AlkB protein. Biochemical and gene knockout mouse studies have confirmed that ABH2 plays an important role in protecting the genome from alkylation damage.

More and more evidence shows that transcription factors are also a factor causing DNA damage. Early bacterial studies revealed a positive correlation between mutation rate and transcription level. The researchers also observed similar results in yeast and mammalian cells. A recent study provided genomic evidence that the mutation rate is higher in highly expressed genes. Various mechanisms have been proposed to explain this phenomenon, including transcription and replication conflicts and the formation of single-stranded DNA. If these damages are not repaired, DNA replication and transcription will be disrupted, eventually causing double-stranded DNA to break.

In this case, cells usually repair DNA damage during transcription by means of transcription-coupled repair. However, it is confusing that although the tandem rDNA gene is the most active transcription gene in mammalian cells, accounting for 70% of the total transcriptional activity in highly proliferating mammalian cells, no RNA polymerase I (RNA polymerase I) was observed. ) The transcribed mammalian rDNA gene undergoes transcription-coupled repair. It is unclear how mammalian cells respond to transcription-related alkylation damage in rDNA genes.

In this article, the researchers reported that the DNA alkylation repair enzyme ABH2 / ALKBH2 was found to be highly enriched in the nucleus. ABH2 interacts with DNA repair enzymes Ku70 and Ku80, as well as nucleolin proteins nucleolin, nucleophosmin 1 and upstream binding factor (UBF). ABH2 binds and promotes rDNA transcription through its DNA repair activity. Inhibition of ABH2 impairs rDNA transcription, leading to increased single- and double-stranded DNA breaks, which is more pronounced in rDNA genes, while overexpression of ABH2 protects cells from methyl-methanesulfonate-induced DNA damage And rDNA transcription inhibition. In response to large amounts of alkylation damage, ABH2 can be quickly relocated from the nucleolus to the nucleoplasm. New research reveals the important role of ABH2 in maintaining rDNA gene integrity and transcription, and provides a new understanding of ABH2 DNA repair function.

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