Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining

Ly, Peter; Teitz, Levi S.; Kim, Dong H.; Shoshani, Ofer; Skaletsky, Helen; Fachinetti, Daniele; Page, David C.; Cleveland, Don W.

doi:10.1038/ncb3450

Cited by 221 publications

(218 citation statements)

References 44 publications

(42 reference statements)

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“…Flp-In T-REx DLD-1 cells were engineered to express the TIR1 auxin-dependent plant E3 ligase, an auxin-inducible degron (AID)-tagged CENP-A modified at the endogenous allele (CENP-A AID/– ), and a doxycycline-inducible CENP-A C–H3 rescue gene integrated into the Flp-In locus as previously described 26 . 4.0 × 10 4 cells were seeded into 4-well chamber slides and treated with doxycycline (DOX, Sigma) and indole-3-acetic acid (IAA, Sigma) for up to 3 days to induce Y chromosome missegregation and micronuclei.…”

Section: Methodsmentioning

confidence: 99%

“…To determine whether missegregated chromosomes provide a source of cytosolic DNA, we employed an inducible Y chromosome-specific missegregation system established in chromosomally stable DLD-1 colorectal cancer cells 26 . Whole-chromosome FISH probes targeting the Y chromosome or an independent autosome (chr15) revealed selective incorporation of the Y chromosome into micronuclei two days following chromosome missegregation induced by doxycycline and auxin (Dox/IAA) treatment.…”

Section: Cin Generates Cytosolic Dnamentioning

confidence: 99%

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Chromosomal instability drives metastasis through a cytosolic DNA response

Bakhoum

Ngo

Laughney

et al. 2018

Nature

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1,103

951

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Chromosomal instability (CIN) is a hallmark of cancer and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling. Genetic suppression of CIN significantly delays metastasis even in highly aneuploid tumor models, whereas inducing continuous chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumor cells co-opt chronic activation of innate immune pathways to spread to distant organs.

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Section: Methodsmentioning

confidence: 99%

Section: Cin Generates Cytosolic Dnamentioning

confidence: 99%

Chromosomal instability drives metastasis through a cytosolic DNA response

Bakhoum

Ngo

Laughney

et al. 2018

Nature

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1,103

951

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“…This conversely implicates the involvement of NHEJ, which is a characteristic of chromothripsis. Given that micronucleus-related chromosome shattering is a mechanism for the origin of chromothripsis, chromosome replication in the micronucleus is not synchronous with that in the nucleus, suggesting that a variable copy number is acceptable in chromothripsis [Crasta et al, 2012;Ly et al, 2017]. Thus, this micronucleus-related chromothripsis pathway may possibly be the mechanism that leads to chromosomal insertion.…”

Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Chromosomal Insertions: Insights into the Mechanisms Underlying Chromothripsis

Kato¹,

Ouchi²,

Inagaki³

et al. 2017

Cytogenet Genome Res

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Chromosomal insertions are rare structural rearrangements, and the molecular mechanisms underlying their origin are unknown. In this study, we used whole genome sequencing to analyze breakpoints and junction sequences in 4 patients with chromosomal insertions. Our analysis revealed that none of the 4 cases involved a simple insertion mediated by a 3-chromosomal breakage and rejoining events. The inserted fragments consisted of multiple pieces derived from a localized genomic region, which were shuffled and rejoined in a disorderly fashion with variable copy number alterations. The junctions were blunt ended or with short microhomologies or short microinsertions, suggesting the involvement of nonhomologous end-joining. In one case, analysis of the parental origin of the chromosomes using nucleotide variations within the insertion revealed that maternal chromosomal segments were inserted into the paternal chromosome. This patient also carried both maternal alleles, suggesting the presence of zygotic trisomy. These data indicate that chromosomal shattering may occur in association with trisomy rescue in the early postzygotic stage.

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“…DNA damage in the form of double-strand breaks (DSBs) resulting in chromosome breakage is also likely involved followed by one or more mechanism(s) of error-prone DNA repair to produce the resulting rearrangements [10]. Many key aspects regarding the cellular mechanisms have emerged over the last five years, including evidence supporting a role of cell division errors in the shattering of an initially missegregated chromosome [24–26]. In this review, we cover recent insights into the mechanisms of chromothripsis with a particular focus on the role of mitotic errors driven by centromere dysfunction.…”

Section: Hidden In Plain Sight: Chromothripsis In the Cancer Genomementioning

confidence: 99%

Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Cleveland

2017

Trends in Cell Biology

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174

166

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Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome missegregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are re-ligated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the cancer genome with localized DNA rearrangements that frequently generate extensive copy number alterations, oncogenic gene fusion products, and/or tumor suppressor gene inactivation. Here we review emerging mechanisms underlying chromothripsis with a focus on the contribution of cell division errors caused by centromere dysfunction.

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Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining

Cited by 221 publications

References 44 publications

Chromosomal instability drives metastasis through a cytosolic DNA response

Chromosomal instability drives metastasis through a cytosolic DNA response

Genomic Characterization of Chromosomal Insertions: Insights into the Mechanisms Underlying Chromothripsis

Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

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