Genome-wide Translocation Sequencing Reveals Mechanisms of Chromosome Breaks and Rearrangements in B Cells

Chiarle, Roberto; Frock, Richard L.; Lewis, Susanna M.; Molinié, Benoit; Ho, Yu-Jui; Myers, David E.; Choi, Vivian W.; Compagno, Mara; Malkin, Daniel J.; Neuberg, Donna; Monti, Stefano; Giallourakis, Cosmas; Gostissa, Monica; Alt, Frederick W.

doi:10.1016/j.cell.2011.12.009

Cited by 105 publications

(184 citation statements)

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“…Accumulating data suggest that AID-dependent DNA damage seems to be one of the major driving forces for variable types of mature B cell-derived lymphomas (47)(48)(49). In the absence of factors from the HR pathway, off-target activity of AID seems to be able to generate numerous non-Ig locus DNA DSBs, dramatically increasing genome instability and B cell cytotoxicity (14).…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cortizas

Verdún

et al. 2015

The Journal of Immunology

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Ig class switching requires cell proliferation and is division linked, but the detailed mechanism is unknown. By analyzing the first switching cells early in the kinetics, our analysis suggested that proliferating B cells had a very short G1 phase (<3.5 h), a total cell cycle time of ∼11 h, and that Ig class switching preferentially occurred in the late G1 or early S phase. Inhibition of cyclin-dependent kinases (CDKs) caused dramatic reduction of switching rate within 6 h. This was associated with less targeting of activation-induced cytidine deaminase (AID) to the Igh locus. Interestingly, ectopically expressed nuclear AID in HeLa cells was preferentially found in the early S phase. Furthermore, in CDK2 hypomorphic cells there was reduced nuclear AID accumulation. Thus, our data are compatible with the idea that division-linked Ig class switching is in part due to CDK2-regulated AID nuclear access at the G1/S border.

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Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cortizas

Verdún

et al. 2015

The Journal of Immunology

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“…DSBs around transcription start sites (TSSs) have been implicated in the transcriptional activation of nuclear hormone receptor genes in tumor cell lines (5,6) and are required for the transcription of a set of early-response genes in activated neurons in culture (7). We also have found that activated B cells in culture generate genomic DSBs at active TSSs, as measured by global nuclear run-on sequencing (GRO-seq) (8) and that these TSS-associated DSBs can translocate to recurrent "bait" DSBs introduced in the body of the c-Myc gene (9).…”

mentioning

confidence: 93%

“…We previously developed an unbiased, high-throughput, genomewide, translocation sequencing (HTGTS) approach to identify DSBs via their translocation to bait DSBs at defined genomic sites in primary progenitor and activated mature B cells, NSPCs, and human cell lines (4,9,(26)(27)(28). Because of cellular heterogeneity in 3D genome organization (3,27,29), HTGTS detects, with great sensitivity, recurrent DSBs in any given genomic location (4,9,(26)(27)(28)(29) or recurrent classes of DSBs, such as DSBs at TSSs, that may occur at much lower frequency in any given location (ref.…”

mentioning

confidence: 99%

Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells

Schwer

Wei

Chang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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High-throughput, genome-wide translocation sequencing (HTGTS) studies of activated B cells have revealed that DNA double-strand breaks (DSBs) capable of translocating to defined bait DSBs are enriched around the transcription start sites (TSSs) of active genes. We used the HTGTS approach to investigate whether a similar phenomenon occurs in primary neural stem/progenitor cells (NSPCs). We report that breakpoint junctions indeed are enriched around TSSs that were determined to be active by global run-on sequencing analyses of NSPCs. Comparative analyses of transcription profiles in NSPCs and B cells revealed that the great majority of TSS-proximal junctions occurred in genes commonly expressed in both cell types, possibly because this common set has higher transcription levels on average than genes transcribed in only one or the other cell type. In the latter context, among all actively transcribed genes containing translocation junctions in NSPCs, those with junctions located within 2 kb of the TSS show a significantly higher transcription rate on average than genes with junctions in the gene body located at distances greater than 2 kb from the TSS. Finally, analysis of repair junction signatures of TSS-associated translocations in wild-type versus classical nonhomologous end-joining (C-NHEJ)–deficient NSPCs reveals that both C-NHEJ and alternative end-joining pathways can generate translocations by joining TSS-proximal DSBs to DSBs on other chromosomes. Our studies show that the generation of transcription-associated DSBs is conserved across divergent cell types.

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“…For example, rrm3 mutant has the same GCR rate as the wild type despite the known role of Rrm3 in preventing replication stalling at hard-to-replicate sites, possibly due to the lack of such sites in the 12-kb region monitored by the GCR assay (Schmidt and Kolodner 2006). Recently, deep sequencing-based methods have been employed to simultaneously identify tens of thousands of translocation junctions without growth selection (Chiarle et al 2011;Klein et al 2011). These approaches rely on an artificial DSB to induce and map translocations and thus are still not bias free.…”

Section: Comparison With Other Methods That Can Reveal Dna Lesion Hotmentioning

confidence: 99%

Mapping genomic hotspots of DNA damage by a single-strand-DNA-compatible and strand-specific ChIP-seq method

Zhou

Zhang

et al. 2012

Genome Res.

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Spontaneous DNA damage may occur nonrandomly in the genome, especially when genome maintenance mechanisms are undermined. We developed single-strand DNA (ssDNA)-associated protein immunoprecipitation followed by sequencing (SPI-seq) to map genomic hotspots of DNA damage. We demonstrated this method with Rad52, a homologous recombination repair protein, which binds to ssDNA formed at DNA lesions. SPI-seq faithfully detected, in fission yeast, Rad52 enrichment at artificially induced double-strand breaks (DSBs) as well as endogenously programmed DSBs for mating-type switching. Applying Rad52 SPI-seq to fission yeast mutants defective in DNA helicase Pfh1 or histone H3K56 deacetylase Hst4, led to global views of DNA lesion hotspots emerging in these mutants. We also found serendipitously that histone dosage aberration can activate retrotransposon Tf2 and cause the accumulation of a Tf2 cDNA species bound by Rad52. SPI-seq should be widely applicable for mapping sites of DNA damage and uncovering the causes of genome instability.

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Genome-wide Translocation Sequencing Reveals Mechanisms of Chromosome Breaks and Rearrangements in B Cells

Cited by 105 publications

References 0 publications

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells

Mapping genomic hotspots of DNA damage by a single-strand-DNA-compatible and strand-specific ChIP-seq method

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