Topoisomerases nick and reseal DNA to relieve torsional stress associated with transcription and replication and to resolve structures such as knots and catenanes. Stabilization of the yeast Top2 cleavage intermediates is mutagenic in yeast, but whether this extends to higher eukaryotes is less clear. Chemotherapeutic topoisomerase poisons also elevate cleavage, resulting in mutagenesis. Here, we describe p.K743N mutations in human topoisomerase hTOP2α and link them to a previously undescribed mutator phenotype in cancer. Overexpression of the orthologous mutant protein in yeast generated a characteristic pattern of 2- to 4-base pair (bp) duplications resembling those in tumors with p.K743N. Using mutant strains and biochemical analysis, we determined the genetic requirements of this mutagenic process and showed that it results from trapping of the mutant yeast yTop2 cleavage complex. In addition to 2- to 4-bp duplications, hTOP2α p.K743N is also associated with deletions that are absent in yeast. We call the combined pattern of duplications and deletions ID_TOP2α. All seven tumors carrying the hTOP2α p.K743N mutation showed ID_TOP2α, while it was absent from all other tumors examined ( = 12,269). Each tumor with the ID_TOP2α signature had indels in several known cancer genes, which included frameshift mutations in tumor suppressors PTEN and TP53 and an activating insertion in BRAF. Sequence motifs found at ID_TOP2α mutations were present at 80% of indels in cancer-driver genes, suggesting that ID_TOP2α mutagenesis may contribute to tumorigenesis. The results reported here shed further light on the role of topoisomerase II in genome instability.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795545 | PMC |
http://dx.doi.org/10.1073/pnas.2114024119 | DOI Listing |
Cell Mol Biol (Noisy-le-grand)
January 2025
Departamento de Biología Molecular y Genómica y Departamento de Disciplinas Filosófico Metodológicas e Instrumentales. Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México.
ABCG2 transporter protein is one of several markers of prostate cancer stem cells (PCSCs). Gene variants of ABCG2 could affect protein expression, function, or both. The aim of this study was to identify the genetic variability of the ABCG2 gene in Mexican patients with prostate cancer.
View Article and Find Full Text PDFPLoS Pathog
January 2025
Department of Microbiology, University of Georgia, Athens, Georgia, United States of America.
The Helicobacter pylori flagellar motor contains several accessory structures that are not found in the archetypal Escherichia coli and Salmonella enterica motors. H. pylori hp0838 encodes a previously uncharacterized lipoprotein and is in an operon with flgP, which encodes a motor accessory protein.
View Article and Find Full Text PDFInt J Syst Evol Microbiol
January 2025
National Fungal Culture Collection of India (NFCCI), Biodiversity and Palaeobiology Group, MACS-Agharkar Research Institute, Pune, India.
Yeast strains representing a novel asexual ascomycetous species were isolated from seven flowers. Sequencing of the chromosomal regions coding for the D1/D2 domains of the large subunit ribosomal RNA, the ITS1-5.8S-ITS2 segments and parts of the gene coding for the small subunit ribosomal RNA showed that the isolates were conspecific.
View Article and Find Full Text PDFBiomedicines
December 2024
Diagnostic and Interventional Neuroradiology Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
The glycosylphosphatidylinositol (GPI) is a glycol-lipid that anchors several proteins to the cell surface. The GPI-anchor pathway is crucial for the correct function of proteins involved in cell function, and it is fundamental in early neurogenesis and neural development. The PIG gene family is a group of genes involved in this pathway with six genes identified so far, and defects in these genes are associated with a rare inborn metabolic disorder manifesting with a spectrum of clinical phenotypes in newborns and children.
View Article and Find Full Text PDFSci Adv
January 2025
Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, NY 10065, USA.
Sensory compensation occurs when loss of one sense leads to enhanced perception by another sense. We have identified a previously undescribed mechanism of sensory compensation in female mosquitoes. Odorant receptor co-receptor () mutants show enhanced attraction to human skin temperature and increased heat-evoked neuronal activity in foreleg sensory neurons.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!