ABSTRACT
The R-loop is a three-stranded nucleic acid structure, which consists of a RNA: DNA hybrid and a DNA single strand. R-loop can be divided into two types: physiological and pathological. The physiological R-loop is involved in many physiological processes such as DNA replication, transcription, and gene expression regulation, while the pathological R-loop induces DNA damage and genome rearrangement. There are many factors that affect the formation of R-loops. Unregulated R-loops destroy genomic stability by interfering with DNA replication and double-strand DNA break repair, and can cause cancer. Therefore, the regulation of R-loops is very important. RNA/ DNA helicase Senataxin (SETX), DEAD-box helicase 5 (DDX5), ribonuclease H (RNase H) and DNA topoisomerase I (topo) play an important role in regulating the balance of R-loops in vivo. Among them, SETX is one of the most characteristic R-loop decomposing enzymes, which can dissolve the R-loops produced during transcriptional termination sites, replication-transcriptional conflicts and DNA damage repair. Senataxin mutations will lead to ataxia with eye movement apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4). Currently there are still many unsolved issues, although many in-depth studies of R-loops have been carried out. Therefore, the structure and function of physiological and pathological R-loops still need to be further explored. This review mainly focuses on the definition and classification of R-loops, the factors that affect the formation of R-loops, the influence of R-loops on genomic stability and R-loop-related diseases, and explores the possibility of using R-loops as a therapeutic target in the future.
ABSTRACT
While Mek1/2 and Gsk3β inhibition ("2i") supports the maintenance of murine embryonic stem cells (ESCs) in a homogenous naïve state, prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential. Additionally, 2i fails to support derivation and culture of fully potent female ESCs. Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin (AlbuMAX) undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture. Mechanistically, lipids in AlbuMAX impact intracellular metabolism including nucleotide biosynthesis, lipid biogenesis, and TCA cycle intermediates, with enhanced expression of DNMT3s that prevent DNA hypomethylation. Lipids induce a formative-like pluripotent state through direct stimulation of Erk2 phosphorylation, which also alleviates X chromosome loss in female ESCs. Importantly, both male and female "all-ESC" mice can be generated from de novo derived ESCs using AlbuMAX-based media. Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.
Subject(s)
Male , Animals , Female , Mice , Mouse Embryonic Stem Cells , Embryonic Stem Cells , Genomic Instability , Lipids , DNA/metabolism , Cell DifferentiationABSTRACT
Gadd45a, a p53 and BRCA1-regulated growth arrest and DNA damage gene, plays important roles in suppressing cell transformation and tumor malignancy. Gadd45a maintains the genomic stability through inhibiting the cell growth and promoting the DNA repair etc, by which it suppresses the tumor development. Additionally, Gadd45a is involved in some important signaling pathway, contributing to its function in tumor suppressing.
ABSTRACT
Objective: To explore the comprehensive effects of folic acid (FA), riboflavin (RF) and MTHFR C677T polymorphism on genomic stability. Method: Cytokinesis-block micronucleus assay was used to detect the effects of different concentration combination of FA (20 and 200nmol/L, i.e. LF and HF) , RF (1 and 500 nmol/L, i.e. LR and HR) and MTHFR C677T polymorphism on genomic stability of 9 d cultured human lymphocytes. Results: The genetic damage was significantly higher in LFHR group regardless the genotype (P