17 research outputs found
Homology-directed repair protects the replicating genome from metabolic assaults
Homology-directed repair (HDR) safeguards DNA integrity under various forms of stress, but how HDR protects replicating genomes under extensive metabolic alterations remains unclear. Here, we report that besides stalling replication forks, inhibition of ribonucleotide reductase (RNR) triggers metabolic imbalance manifested by the accumulation of increased reactive oxygen species (ROS) in cell nuclei. This leads to a redox-sensitive activation of the ATM kinase followed by phosphorylation of the MRE11 nuclease, which in HDR-deficient settings degrades stalled replication forks. Intriguingly, nascent DNA degradation by the ROS-ATM-MRE11 cascade is also triggered by hypoxia, which elevates signaling-competent ROS and attenuates functional HDR without arresting replication forks. Under these conditions, MRE11 degrades daughter-strand DNA gaps, which accumulate behind active replisomes and attract error-prone DNA polymerases to escalate mutation rates. Thus, HDR safeguards replicating genomes against metabolic assaults by restraining mutagenic repair at aberrantly processed nascent DNA. These findings have implications for cancer evolution and tumor therapy
Rectal mucosal prostaglandin E2 release and its relation to disease activity, electrical potential difference, and treatment in ulcerative colitis.
THE INTER-RELATIONSHIP OF THYROID HORMONES, VITAMIN A AND THEIR BINDING PROTEINS FOLLOWING ACUTE STRESS
Selective Oxidation of a 0.1C-6Mn-2Si Third Generation Advanced High-Strength Steel During Dew-Point Controlled Annealing
7-week aerobic exercise training reduces adipocyte area and improves insulin sensitivity in Wistar rats fed a highly palatable diet
Glucosinolate Breakdown in Arabidopsis: Mechanism, Regulation and Biological Significance
Glucosinolates are a group of thioglucosides in plants of the Brassicales order. Together with their hydrolytic enzymes, the myrosinases, they constitute the ‘mustard oil bomb’ involved in plant defense. Here we summarize recent studies in Arabidopsis that have provided molecular evidence that the glucosinolate-myrosinase system is much more than a ‘two-component defense system,’ and started to unravel the roles of different glucosinolate breakdown pathways in the context of plant responses to biotic and abiotic stresses