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Total protein abundances upon Mcm6 knockdown in the murine CH12 cells

ABSTRACT: 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

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood

SUBMITTER: Richard Imre

LAB HEAD: Rushad Rusi Pavri

PROVIDER: PXD034446 | Pride | 2022-09-13

REPOSITORIES: Pride

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			Action	DRS
	20200904_QExHFX4_RSLC4_Peycheva_Pavri_IMP_TMT6plex_65fr_Mouse_Limma_SpikeIns-_1_.pdResult	Other
	20200904_QExHFX4_RSLC4_Peycheva_Pavri_IMP_TMT_10p_SCX_FR27.raw	Raw
	20200904_QExHFX4_RSLC4_Peycheva_Pavri_IMP_TMT_10p_SCX_FR28.raw	Raw
	20200904_QExHFX4_RSLC4_Peycheva_Pavri_IMP_TMT_10p_SCX_FR29.raw	Raw
	20200904_QExHFX4_RSLC4_Peycheva_Pavri_IMP_TMT_10p_SCX_FR30.raw	Raw

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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.

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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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Project description:Translocations, that occur when two DNA Double Strand breaks (DSBs) are abnormally rejoined, represent highly deleterious genome rearrangements favoring cancer apparition and progression. However, the mechanisms that drive their formation are yet poorly deciphered. One prerequisite for translocation is the juxtaposition of two distant DSBs, an event that would be favored if DSB cluster, i.e. are brought together in close spatial proximity within the nucleus. Whether DSB cluster in higher eukaryotes has been subjected to a strong controversy over the past decade, due to conflicting results obtained using microscopy based methods1-9. Here we used for the first time a high throughput chromosome conformation capture assay (Capture Hi-C10) to investigate DSB clustering. We unambiguously found that DSBs do cluster in human nuclei but only when induced in transcriptionally active genes. Clustering of damaged genes mainly occur during the G1 cell cycle phase and coincide with delayed repair. Moreover DSB clustering depends on the MRN complex, as well as the Formin 2 (FMN2) nuclear actin organizer and the LINC (LInker of Nuclear and Cytoplasmic skeleton) complex, suggesting that active mechanisms promote DSB clustering. This work reveals that when damaged, active genes exhibit a very peculiar behavior compared to the rest of the genome, being mostly left unrepaired and clustered in G1 while being repaired by homologous recombination in post-replicative cells.

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