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| Status |
Public on Sep 15, 2022 |
| Title |
DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [Repli-seq] |
| Organism |
Mus musculus |
| Experiment type |
Other
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| 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.
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| Overall design |
Repli-seq in LacZ and Mcm infected CH12 cells and C13, C2ki and C13ki clones
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| Contributor(s) |
Peycheva M, Neumann T, Malzl D, Nazarova M, Schoeberl UE, Pavri R |
| Citation(s) |
36108018 |
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| Submission date |
Nov 19, 2020 |
| Last update date |
Dec 15, 2022 |
| Contact name |
Tobias Neumann |
| Organization name |
IMP
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| Street address |
Campus-Vienna-Biocenter 1
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| City |
Vienna |
| ZIP/Postal code |
1030 |
| Country |
Austria |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (32)
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| This SubSeries is part of SuperSeries: |
| GSE161822 |
DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations |
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| Relations |
| BioProject |
PRJNA679572 |
| SRA |
SRP293271 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE161819_CH12_RT_C13KI_loess.bw |
7.0 Mb |
(ftp)(http) |
BW |
| GSE161819_CH12_RT_C13_loess.bw |
7.0 Mb |
(ftp)(http) |
BW |
| GSE161819_CH12_RT_C2KI_loess.bw |
7.0 Mb |
(ftp)(http) |
BW |
| GSE161819_CH12_RT_WTKI_loess.bw |
7.0 Mb |
(ftp)(http) |
BW |
| GSE161819_CH12_RT_WT_loess.bw |
7.0 Mb |
(ftp)(http) |
BW |
| GSE161819_CH12_RT_shLacZ_loess.bw |
7.0 Mb |
(ftp)(http) |
BW |
| GSE161819_CH12_RT_shMcm_loess.bw |
7.1 Mb |
(ftp)(http) |
BW |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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