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Series GSE161820 Query DataSets for GSE161820
Status Public on Sep 15, 2022
Title DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [RNA-seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Many cancers originate from misregulation of gene expression caused by chromosomal translocations which result from ligation of DNA double-strand breaks (DSBs). Indeed, translocations may be causal in ~20% of human cancer morbidity 1. Although the sources of DSBs are numerous2-5, we have virtually no knowledge of the steps linking DSB formation to DSB ligation. Here, we show that early replication timing of translocation partner loci, mediated by the activity of replication origins, is a critical regulator of lymphomagenic Myc translocations generated by activation-induced deaminase (AID) during antibody maturation in B-cells. Reduced levels of the replicative helicase, the minichromosome maintenance (MCM) complex6, impairs translocation genesis, decreases firing of replication origins at AID target genes and globally abrogates the replication timing program without altering cell proliferation, gene expression or genome architecture. Strikingly, deleting a single origin of replication at Myc induces a switch from early-to-late replication at Myc with concomitantly impaired translocation frequency. This phenotype is reversed by restoring early replication at Myc thereby demonstrating a direct, causal role of replication origin activity and replication timing in translocation genesis. Finally, this replication timing-mediated step acts downstream of DSBs and is independent of DSB frequency, constituting a novel regulatory step in translocation biogenesis.
Overall design RNA-Seq LacZ and Mcm infected CH12 cells and C13 and C23 clones
Contributor(s) Peycheva M, Neumann T, Malzl D, Nazarova M, Schoeberl UE, Pavri R
Citation(s) 36108018
Submission date Nov 19, 2020
Last update date Dec 15, 2022
Contact name Tobias Neumann
Organization name IMP
Street address Campus-Vienna-Biocenter 1
City Vienna
ZIP/Postal code 1030
Country Austria
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (15)
GSM4915207 CH12_RNASeq_shLacZ_d3_rep1
GSM4915208 CH12_RNASeq_shLacZ_d3_rep2
GSM4915209 CH12_RNASeq_shLacZ_d3_rep3
This SubSeries is part of SuperSeries:
GSE161822 DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations
BioProject PRJNA679573
SRA SRP293272

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Supplementary file Size Download File type/resource
GSE161820_CH12_RNASeq_quantifications.txt.gz 450.6 Kb (ftp)(http) TXT
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