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DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [PRO-cap]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE171623 | GEO | 2022/09/15

REPOSITORIES: GEO

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DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations [SNS-seq]

Project description: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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Total protein abundances upon Mcm6 knockdown in the murine CH12 cells

Project description:Chromosomal translocations result from joining of DNA double-strand breaks (DSBs) and frequently cause cancer. Yet, the steps linking DSB formation to DSB ligation remain undeciphered. We report that DNA replication timing (RT) directly regulates lymphomagenic Myc translocations during antibody maturation in B-cells downstream of DSBs and independently of DSB frequency. Depletion of minichromosome-maintenance (MCM) complexes alters replication origin activity, decreases translocations and abrogates global RT. Ablating a single origin at Myc causes an early-to-late RT switch, loss of translocations and reduced nuclear proximity with a translocation partner locus, phenotypes that were reversed by restoring early RT. Disruption of shared early RT also reduced tumorigenic translocations in human leukemic cells. Thus, RT constitutes a new, unprecedented mechanism in translocation biogenesis linking DSB formation to DSB ligation

2022-09-13 | PXD034446 | Pride

DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations

Project description:Chromosomal translocations result from the joining of DNA double-strand breaks (DSBs) and frequentlycause cancer. However, the steps linking DSB formation to DSB ligation remain undeciphered. Wereport that DNA replication timing (RT) directly regulates lymphomagenicMyctranslocations duringantibody maturation in B cells downstream of DSBs and independently of DSB frequency. Depletion ofminichromosome maintenance complexes alters replication origin activity, decreases translocations,and deregulates global RT. Ablating a single origin atMyccauses an early-to-late RT switch, loss oftranslocations, and reduced proximity with the immunoglobulin heavy chain (Igh) gene, its majortranslocation partner. These phenotypes were reversed by restoring early RT. Disruption of early RT alsoreduced tumorigenic translocations in human leukemic cells. Thus, RT constitutes a general mechanismin translocation biogenesis linking DSB formation to DSB ligation.

2022-09-15 | GSE161818 | GEO

High-throughput sequencing of genome-wide translocations from stimulated wild-type or ATM-deficient B cells

Project description:High-throughput genome-wide translocation sequencing (HTGTS) is a robust approach to identify genome-wide translocation junctions. We performed HTGTS to study the fate of introduced c-myc DSBs in mouse splenic B cells activated for activation cytidine deaminase (AID)-dependent class switch recombination (CSR). We found frequent translocations of c-myc DSBs to AID-initiated DSBs in IgH switch regions in wild-type (WT) and ATM-deficient B cells. However, c-myc also translocated frequently to newly generated DSBs within a 35-megabase region downstream of IgH in ATM-deficient, but not WT, CSR-activated B cells. Moreover, we found such DSBs and translocations in activated B cells that did not express AID or undergo CSR. These findings indicate that ATM deficiency leads to formation of chromosome 12 dicentrics via RAG-initiated IgH DSBs in progenitor B cells and that these dicentrics can be propagated developmentally into mature B cells where they generate new DSBs downstream of IgH via breakage-fusion-bridge cycles. Preparation of libraries from WT or ATM-deficient activated by a-CD40/IL4 or RP105.

2014-06-18 | E-GEOD-58599 | biostudies-arrayexpress

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Rec114 ChIP-seq

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2014-07-21 | E-GEOD-52970 | biostudies-arrayexpress

DNA double-strand breaks induced by AID in activated splenic B cells

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2015-07-16 | GSE66424 | GEO

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