Nuclear chromosome location dictates segregation error frequency
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ABSTRACT:
PROVIDER: PRJEB52892 | ENA |
REPOSITORIES: ENA
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Project description:Spindle assembly checkpoint (SAC) regulators such as the Mps1 kinase not only delay anaphase onset, but also correct improper chromosome-spindle linkages that would otherwise lead to missegregation and aneuploidy. However, the substrates and mechanisms involved in this pathway of error correction remain poorly understood. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K-fibers) epistatically to Aurora B, the other major error-correcting kinase. Through chemical genetics and quantitative proteomics, we identify both known and novel sites of Mps1- regulated phosphorylation at the outer kinetochore. Modification of these substrates was sensitive to microtubule tension and counterbalanced by the PP2A-B56 phosphatase, a positive regulator of chromosome-spindle interactions. Consistently, Mps1 inhibition rescued K-fiber stability after depleting PP2A-B56. We also identify the hinge region of the W-shaped Ska complex as a key effector of Mps1 at the kinetochore-microtubule interface, as mutations that mimic constitutive phosphorylation strongly destabilized K-fibers in vivo and inhibited the Ska complex’s conversion from lattice diffusion to end-coupled microtubule binding in vitro. Together these results provide new insights into how Mps1 modulates the microtubule-binding properties of the kinetochore to promote the selective stabilization of bipolar attachments and error-free chromosome segregation.
2018-10-24 | PXD006135 | Pride
Project description:Preservation of a balanced chromosomal content is regarded to be a key point for the success of multicellular organisms. Chromosomal segregation takes place under the strict control of well-orchestrated cell-cycle checkpoints, consequently leading to accurate transmission of intact chromosomes. Estimates of the whole chromosomal error rates per cell division based on cytogenetic analyses of newborns and products of conception, range between 4.57x10-5 and 3.42x10-4. Recent sporadic studies of single cell genome wide CNV analysis suggested that the error rate might be higher than currently estimated. To obtain accurate measures of chromosomal error rates, we plated single fibroblast and analyzed the two daughter sister cells following a single cell division. In total 14 single fibroblasts derived from 7 mitoses carried segmental aneuploidies in a total of 178 cells from 5 different cell lines that were analyzed after a single cell division, indicating a mean frequency of 7.9% in vitro. In conclusion, the chromosomal stability is hundreds times lower than the current dogma, showing that chromosomal instability is a common place and putting the efficacy of the DNA-repair mechanisms and control checkpoints in question.
2016-05-01 | GSE75069 | GEO
Project description:Genome location dictates the transcriptional response to sub-inhibitory concentrations of PolC-inhibitors in Clostridium difficile
| PRJNA478856 | ENA
Project description:Liver Cancer Evolution - Lesion segregation
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Project description:Meiosis produces gametes through a specialised, two-step cell division, which is highly error-prone in humans. Reductional meiosis I, where maternal and paternal chromosomes (homologs) segregate, is followed by equational meiosis II, where sister chromatids separate. Uniquely during meiosis I, sister kinetochores are monooriented and pericentromeric cohesin is protected. Here, we demonstrate that these key adaptations for reductional chromosome segregation are achieved through separable control of multiple kinases by the meiosis I-specific budding yeast Spo13 protein. Recruitment of Polo kinase to kinetochores directs monoorientation, while, independently, cohesin protection is achieved by controlling the effects of cohesin kinases. Therefore, reductional chromosome segregation, the defining feature of meiosis, is established by multifaceted kinase control by a master regulator. The recent identification of Spo13 orthologs, fission yeast Moa1 and mouse MEIKIN, suggests that kinase coordination by a master meiosis I regulator may be a general feature in the establishment of reductional chromosome segregation.
2019-11-13 | PXD012627 | Pride
Project description:Transcription occurs ubiquitously throughout non-coding parts of the genome, including at repetitive alpha-satellite DNA elements which comprise the majority of human centromeres. The function of temporally regulated centromeric transcription, and transcripts, is consequently a topic of intense investigation. In this study, we use high throughput approaches to identify and describe lncRNAs associated with the centromere specific histone variant CENP-A that arise from the transcription of specific centromeres at early G1, which we then show are physically associated with centromeres, and which are functionally necessary for accurate chromosome segregation. Targeted depletion of one such centromeric RNA, which originates from a single centromere, is sufficient to increase the frequency of chromosome segregation defects. These data support the emerging paradigm of the necessity of centromere-specific lncRNAs in the integrity of faithful chromosome segregation.
2019-11-26 | GSE137377 | GEO
Project description:NEI Refractive Error Collaboration (KORA)
| PRJNA75817 | ENA
Project description:Assessment of technical error in a dual-channel, two timepoint experiment using White lab Drosophila melanogaster microarrays
2010-06-10 | E-GEOD-2641 | biostudies-arrayexpress
Project description:Assessment of technical error in a dual-channel, two timepoint experiment using White lab Drosophila melanogaster microarrays Keywords: repeat sample
2005-05-12 | GSE2641 | GEO