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Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress

ABSTRACT: Human development relies on the correct replication, maintenance and segregation of our genetic blueprints. How these processes are monitored across embryonic lineages, and why genomic mosaicism varies during development remain unknown. Using pluripotent stem cells, we identify that several patterning signals –including WNT, BMP and FGF– converge into the modulation of DNA replication stress and damage during S-phase, which in turn controls chromosome segregation fidelity in mitosis. We show that the WNT and BMP signals protect from excessive origin firing, DNA damage and chromosome missegregation derived from stalled forks in pluripotency. Cell signalling control of chromosome segregation declines during lineage specification into the three germ layers, but re-emerges in neural progenitors. In particular, we find that the neurogenic factor FGF2 induces DNA replication stress-mediated chromosome missegregation during the onset of neurogenesis, which could provide a rationale for the elevated chromosomal mosaicism of the developing brain. Our results highlight roles for morphogens and cellular identity in genome maintenance that contribute to somatic mosaicism during mammalian development.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hipsc Cell

SUBMITTER: Anchel de Jaime Soguero

LAB HEAD: Prof. Sergio P. Acebron

PROVIDER: PXD054388 | Pride | 2024-07-31

REPOSITORIES: Pride

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			Action	DRS
	UP000005640_9606.fasta	Fasta
	oecf3-GP0528-01.raw	Raw
	oecf3-GP0528-02.raw	Raw
	oecf3-GP0528-03.raw	Raw
	oecf3-GP0528-04.raw	Raw

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Developmental signals control chromosome segregation fidelity during early lineage specification and neurogenesis by modulating replicative stress

Project description:Human development and homeostasis rely on the correct replication, maintenance and segregation of our genetic blueprints. How these intracellular processes are monitored across different human cellular lineages, and why the spatio-temporal distribution of mosaicism varies during development remain unknown. Using human and mouse pluripotent stem cells, we identify that several lineage specification signals –including WNT, BMP and FGF– converge into the modulation of DNA replication stress and damage during S-phase, which in turn controls spindle dynamics and chromosome segregation fidelity in mitosis. We show that patterning signals associated with anteriorisation during mammalian gastrulation increase chromosome missegregation, while the posteriorising signals WNT and BMP protect pluripotent stem cells from excessive origin firing, DNA damage and chromosome missegregation derived from stalled forks. Through epistasis experiments, we find that WNT, BMP and FGF have distinct roles during DNA replication, and demonstrate that WNT/GSK3 signalling sits at the helm of this regulatory cascade. Cell signalling control of chromosome segregation declines after pluripotency exit and specification into the three human germ layers, but re-emerges in differentiating neural progenitors. Through ex vivo and in vivo analyses, we also show that FGF and WNT signalling display opposite roles in chromosome segregation fidelity in mouse neural progenitors during the onset of neurogenesis (E14.5), but not during their expansion (E12.5). In particular, we find that the neurogenic factor FGF2 induces DNA replication stress-mediated chromosome missegregation, which could provide a rationale for the elevated chromosomal mosaicism of the developing brain. Our results highlight a role for patterning signals and cellular identity in genome maintenance that contributes to somatic mosaicism during mouse and human early lineage specification and neurogenesis.

2024-07-08 | GSE271478 | GEO

Mass spectrometry analysis of in vitro PLK1 phosphorylation

Project description:Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate PLK1 in mitosis remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.

2024-11-01 | PXD053933 | Pride

Re-replication generates whole-chromosomal instability and anueploidy

Project description:Aneuploidy, a hallmark of cancer, often arises from whole-chromosomal instability (W-CIN). Many cancers exhibiting W-CIN, however, show no direct insult to the mitotic proteins that ensure proper segregation of chromosomes. This has stimulated interest in identifying defects in non-mitotic processes that might disrupt chromosome behavior in mitosis. Here we show in Saccharomyces cerevisiae that transient re-replication of centromeric DNA, due to deregulation of replication initiation proteins, greatly induces aneuploidy of the rereplicated chromosome. Some of this aneuploidy appears to arise from simple missegregation of both sister chromatids to one daughter cell, indicating that centromeric re-replication can disrupt proper centromere function during mitosis. Another source of aneuploidy appears to be the generation of an extra sister chromatid via homologous recombination, suggesting that centromeric rereplication can trigger breakage and repair events that expand chromosome numbers while preserving chromosome structure. Given the emerging connections between the deregulation of replication initiation proteins and oncogenesis, our findings offer the possibility of a new non-mitotic source of aneuploidy that may be relevant to cancer.

2014-07-25 | GSE55641 | GEO

Re-replication generates whole-chromosomal instability and anueploidy

Project description:Aneuploidy, a hallmark of cancer, often arises from whole chromosome instability (W-CIN). Many cancers exhibiting W-CIN, however, show no direct insult to the mitotic proteins that ensure proper segregation of chromosomes. This has stimulated interest in identifying defects in non-mitotic processes that might disrupt chromosome behavior in mitosis. Here we show in Saccharomyces cerevisiae that re-replication of centromeric DNA, caused by deregulation of replication initiation proteins, efficiently induces chromosome instability––either by causing missegregation of both sister chromatids to one daughter cell or by triggering formation of an extra chromatid through a pathway dependent on homologous recombination. Given the emerging connections between the deregulation of replication initiation proteins and oncogenesis, our findings offer the possibility of a new non-mitotic source of W-CIN and aneuploidy that may be relevant to cancer. Diploid strains containing a re-replicating locus were induced to re-replicate through a centromere. This compilation includes the analysis of the re-replication, as well as the copy-number determination of alleged aneuploid colonies from various backgrounds. Series contains a total of 194 copy number hybridizations and 8 re-replication profile hybridizations. Note that the VALUE field reported for all of the sample tables in this series are the log2 of the normalized Cy3/Cy5 ratio. To convert these into usable copy number profiles raise 2 to the indicated VALUE.

2014-07-25 | E-GEOD-55641 | biostudies-arrayexpress

Cell non-autonomous regulation of chromosome segregation

Project description:Chromosome segregation has been assumed to be a cell-autonomous process. We tested this assumption by comparing chromosome segregation fidelity in epithelial cells in various contexts and discovered that these cells have increased chromosome missegregation outside of their native tissue. Using organoid culture systems, we show that tissue architecture, specifically integrin function, is required for accurate chromosome segregation in epithelia. We find that tissue architecture enhances the correction of merotelic microtubule-kinetochore attachments, and this is critically important for maintaining chromosome stability in the polyploid liver. Our data lead to the surprising conclusion that chromosome segregation in epithelia is a cell non-autonomous process. We propose that disruption of tissue architecture could underlie the chromosome instability that characterizes and drives epithelial cancers. Moreover, our findings highlight the importance of context for fundamental cellular processes and caution against the exclusive reliance on cell culture systems for deciphering and manipulating mammalian biology.

2018-08-23 | GSE111078 | GEO

Genome-wide ParB2-DNA and RctB-DNA interaction analyses in Vibrio cholerae

Project description:Replication and segregation are the two main processes that maintain chromosomes in growing cells. In bacteria, replication and transcription have been proposed to provide motive force in chromosome segregation. Recently, ParB2, a segregation protein, encoded by V. cholerae chromosome II (chrII) was also found to influence chrII replication. V. cholerae chrII replication is primarily controlled by its specific initiator protein, RctB. Here, we have screened for ParB2 and RctB binding sites using a genome-wide DNA binding analysis (ChIP-chip). We report the identification of a new region containing additional RctB and ParB2 binding sites, and suggest the mechanisms to coordinate replication initiation with segregation of chromosomes. ParB2 binding DNA (Cy5) vs total DNA (input, Cy3) in wildtype (CVC209), RctB binding DNA (Cy5) vs total DNA (input, Cy3) in wildtype (CVC209), RctB binding DNA (Cy5) vs total DNA (input, Cy3) in MCH1 (CVC2099, rctB-deleted strain), Biological replicates: 3 or 2

2015-09-14 | E-GEOD-72978 | biostudies-arrayexpress

Genome-wide ParB2-DNA and RctB-DNA interaction analyses in Vibrio cholerae

2015-09-14 | GSE72978 | GEO

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Mapping of cohesion factor association sites in S. cerevisiae - Meiosis I chromosome segregation is established through regulation of microtubule-kinetochore interactions.

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