Downregulation Of Repair Genes Research Articles

Curcumin alleviates persistence of Acinetobacter baumannii against colistin

Persisters are phenotypic variants of normal susceptible bacterial populations that survive prolonged exposure to high doses of antibiotics and are responsible for pertinacious infections and post-treatment relapses. Out of the three antibiotics, Acinetobacter baumannii formed the highest percentage of persister cells against rifampicin followed by amikacin and the least against colistin. Colistin-treated cells formed the high levels of reactive oxygen species (ROS) whose quenching with bipyridyl and thiourea led to an increased persister population. Curcumin, a polyphenolic pro-oxidant, significantly decreased persistence against colistin. The quenching of ROS generated by curcumin-colistin combination and the use of resveratrol, an anti-oxidant, with colistin increased the persister population, supporting the significance of ROS in decreased persistence against this combination. The down-regulation of repair genes by this combination in comparison to colistin alone supported the modulation of gene expression in response to ROS and their importance in decreased persistence. Increased membrane permeability by colistin, facilitating the penetration of curcumin into cells and resulting in increased ROS and compromised repair compounded by the decreased efflux of colistin by the inhibition of efflux pumps, may be responsible for enhanced lethality and low persistence. Hence, the curcumin-colistin combination can be another option with anti-persister potential for the control of chronic A. baumannii infections.

Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor

BackgroundHistone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregulation remains unclear. Here we provide evidence that several DNA repair genes are downregulated by HDAC inhibition and provide a mechanism involving the E2F1 transcription factor in the process.Methodology/Principal FindingsApplying Analysis of Functional Annotation (AFA) on microarray data of prostate cancer cells treated with HDACis, we found a number of genes of the DNA damage response and repair pathways are downregulated by HDACis. AFA revealed enrichment of homologous recombination (HR) DNA repair genes of the BRCA1 pathway, as well as genes regulated by the E2F1 transcription factor. Prostate cancer cells demonstrated a decreased DNA repair capacity and an increased sensitization to chemical- and radio-DNA damaging agents upon HDAC inhibition. Recruitment of key HR repair proteins to the site of DNA damage, as well as HR repair capacity was compromised upon HDACi treatment. Based on our AFA data, we hypothesized that the E2F transcription factors may play a role in the downregulation of key repair genes upon HDAC inhibition in prostate cancer cells. ChIP analysis and luciferase assays reveal that the downregulation of key repair genes is mediated through decreased recruitment of the E2F1 transcription factor and not through active repression by repressive E2Fs.Conclusions/SignificanceOur study indicates that several genes in the DNA repair pathway are affected upon HDAC inhibition. Downregulation of the repair genes is on account of a decrease in amount and promoter recruitment of the E2F1 transcription factor. Since HDAC inhibition affects several pathways that could potentially have an impact on DNA repair, compromised DNA repair upon HDAC inhibition could also be attributed to several other pathways besides the ones investigated in this study. However, our study does provide insights into the mechanism that governs downregulation of HR DNA repair genes upon HDAC inhibition, which can lead to rationale usage of HDACis in the clinics.