scholarly journals Loss of BubR1 Acetylation instigates Replication Stress leading to Complex Chromosomal Rearrangement in tumors

2019 ◽  
Author(s):  
Jiho Park ◽  
Song-Yion Yeu ◽  
Sangjin Paik ◽  
Junyeob Lee ◽  
Jinho Jang ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Chromosome Structure ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Chromosome Rearrangements ◽  
Mouse Tumors ◽  
Genome Wide ◽  
Deficient Mice ◽  
Complex Chromosome ◽  
Double Mutant Mouse

AbstractChromosome number and structure instability is the hallmark of cancer. Equal chromosome segregation is guaranteed by the spindle assembly checkpoint (SAC), thus defective SAC leads to chromosome instability. However, aneuploidy alone is not oncogenic, and whether compromised SAC is associated with structure instability remains elusive. BubR1 is a core component of SAC, which is acetylated at lysine 250 in mitosis. Previously, we showed that deficiency of BubR1 acetylation in mice (K243R/+) leads to spontaneous tumorigenesis via chromosome mis-segregation. Here, we asked whether loss of BubR1 acetylation is associated with chromosome structure instability by examiningK243R/+mice intercrossed top53-deficient mice. Genome-wide sequencing and spectral karyotyping of the double mutant mouse tumors revealed that BubR1 acetylation deficiency leads to complex chromosome rearrangements, including Robertsonian-like whole-arm translocations and premature sister-chromatid separations (PMSCS). In primary MEFs, replication stress was markedly increased in telomeres and centromeres, suggesting that the replication stress underlies the significant increase of DNA damage and subsequent chromosome rearrangements. Furthermore, defects in BubR1 acetylation at K250 were detected in human cancers as well. Collectively, we propose that chromosome mis-segregation by the loss of BubR1 acetylation causes chromosome structure instability, leading to massive chromosome rearrangements through the induction of replication stress.

Chromosome Imbalances in Cancer: Molecular Cytogenetics Meets Genomics

2016 ◽  
Vol 150 (3-4) ◽  
pp. 176-184 ◽  
Author(s):  
Elisa Palumbo ◽  
Antonella Russo
Keyword(s):  
Cancer Research ◽  
Cancer Cells ◽  
Genomic Instability ◽  
Molecular Cytogenetics ◽  
Chromosome Rearrangements ◽  
Multicolor Fish ◽  
Genome Wide ◽  
Chromosome Imbalances ◽  
Complex Chromosome

Genomic instability is a hallmark of cancer, and it is well-known that in several cancers the karyotype is unstable and rapidly evolving. Molecular cytogenetics has contributed to the description and interpretation of cancer karyotypes, in particular through multicolor FISH approaches which can define even complex chromosome rearrangements. The introduction of genome-wide methods has made available a powerful set of tools with higher resolution than cytogenetics, thus appropriate to comprehend the huge variability of cancer cells. This review focuses on novel findings deriving from the combination of cytogenetic and genomic approaches in cancer research.

scholarly journals Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Athea Vichas ◽  
Amanda K. Riley ◽  
Naomi T. Nkinsi ◽  
Shriya Kamlapurkar ◽  
Phoebe C. R. Parrish ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Genetic Data ◽  
Multiple Models ◽  
Ras Pathway ◽  
Functional Interactions ◽  
Genome Wide ◽  
A Genome ◽  
Mutant Cells

AbstractCRISPR-based cancer dependency maps are accelerating advances in cancer precision medicine, but adequate functional maps are limited to the most common oncogenes. To identify opportunities for therapeutic intervention in other rarer subsets of cancer, we investigate the oncogene-specific dependencies conferred by the lung cancer oncogene, RIT1. Here, genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells identifies shared and unique vulnerabilities of each oncogene. Combining this genetic data with small-molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. Oncogenic RIT1M90I weakens the spindle assembly checkpoint and perturbs mitotic timing, resulting in sensitivity to Aurora A inhibition. In addition, we observe synergy between mutant RIT1 and activation of YAP1 in multiple models and frequent nuclear overexpression of YAP1 in human primary RIT1-mutant lung tumors. These results provide a genome-wide atlas of oncogenic RIT1 functional interactions and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

scholarly journals DNA-Replikationsstress, Mitose und genomische Instabilität

BIOspektrum ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 10-13
Author(s):  
Alicia Konrath ◽  
Ann-Kathrin Schmidt ◽  
Holger Bastians
Keyword(s):  
Dna Replication ◽  
Tumor Progression ◽  
Chromosome Aberrations ◽  
Chromosomal Instability ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Functional Link ◽  
Structural Chromosome ◽  
Genomische Instabilität

AbstractChromosomal instability (CIN) is a hallmark of cancer and contributes to tumorigenesis and tumor progression. While structural CIN (S-CIN) leads to structural chromosome aberrations, whole chromosome instability (W-CIN) is defined by perpetual gains or losses of chromosomes during mitosis causing aneuploidy. Mitotic defects, but also abnormal DNA replication (replication stress) can lead to W-CIN. However, the functional link between replication stress, mitosis and aneuploidy is little understood.

scholarly journals Replication Stress and Telomere Dysfunction Are Present in Cultured Human Embryonic Stem Cells

2015 ◽  
Vol 146 (4) ◽  
pp. 251-260 ◽  
Author(s):  
Christine Janson ◽  
Kristine Nyhan ◽  
John P. Murnane
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Chromosome Instability ◽  
Embryonic Stem ◽  
Replication Stress ◽  
Activin A ◽  
Fragile Sites ◽  
Telomere Dysfunction

Replication stress causes DNA damage at fragile sites in the genome. DNA damage at telomeres can initiate breakage-fusion-bridge cycles and chromosome instability, which can result in replicative senescence or tumor formation. Little is known about the extent of replication stress or telomere dysfunction in human embryonic stem cells (hESCs). hESCs are grown in culture with the expectation of being used therapeutically in humans, making it important to minimize the levels of replication stress and telomere dysfunction. Here, the hESC line UCSF4 was cultured in a defined medium with growth factor Activin A, exogenous nucleosides, or DNA polymerase inhibitor aphidicolin. We used quantitative fluorescence in situ hybridization to analyze individual telomeres for dysfunction and observed that it can be increased by aphidicolin or Activin A. In contrast, adding exogenous nucleosides relieved dysfunction, suggesting that telomere dysfunction results from replication stress. Whether these findings can be applied to other hESC lines remains to be determined. However, because the loss of telomeres can lead to chromosome instability and cancer, we conclude that hESCs grown in culture for future therapeutic purposes should be routinely checked for replication stress and telomere dysfunction.

scholarly journals An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer

2020 ◽  
Author(s):  
Athea Vichas ◽  
Naomi T. Nkinsi ◽  
Amanda Riley ◽  
Phoebe C.R. Parrish ◽  
Fujiko Duke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Hippo Pathway ◽  
Spindle Assembly ◽  
Human Lung Cancer ◽  
Precision Oncology ◽  
Cancer Driver ◽  
Molecular Alterations ◽  
Pathway Gene ◽  
Genome Wide

ABSTRACTAdvances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor’s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred by lung cancer driver variants of KRAS, EGFR, and RIT1. Integrative analysis of genome-wide CRISPR screens in isogenic cell lines identified shared and unique vulnerabilities of each oncogene. The non-identical landscape of dependencies underscores the importance of genotype-guided therapies to maximize tumor responses. Combining genetic screening data with small molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. This sensitivity may be related to a novel role of RIT1 in mitosis; we find that oncogenic RIT1M90I alters mitotic timing via weakening of the spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutant RIT1 with loss of Hippo pathway genes. In human lung cancer, RIT1 mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenic RIT1-cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

scholarly journals Microvasculopathy, Luminal Calcification and Premature Aging in Fetuin-A Deficient Mice

2019 ◽  
Author(s):  
Marietta Herrmann ◽  
Anne Babler ◽  
Irina Moshkova ◽  
Felix Gremse ◽  
Fabian Kiessling ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Early Stage ◽  
Analytical Electron Microscopy ◽  
Premature Aging ◽  
Fetuin A ◽  
Genome Wide ◽  
Ectopic Mineralization ◽  
Brown Adipose ◽  
Calciprotein Particles ◽  
Deficient Mice

AbstractObjectiveThe plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP) – rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore ectopic mineralization (calcification). The mutant mouse strain D2,Ahsg-/- combines fetuin-A deficiency with the mineralization-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue mineralization. Here we studied mechanisms leading to soft tissue mineralization, organ damage and premature aging in these mice.Approach and ResultsWe analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/- mice.Fetuin-A deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature aging. Importantly, early stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the ectopic mineralization was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis.ConclusionsCollectively, these results demonstrate that pathological mineralization can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of mineralized matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.

Usefulness and limitations of FISH to characterize partially cryptic complex chromosome rearrangements

2000 ◽  
Vol 95 (1) ◽  
pp. 28-35 ◽  
Author(s):  
Kathleen A. Kaiser-Rogers ◽  
Kathleen W. Rao ◽  
Ron C. Michaelis ◽  
Christa M. Lese ◽  
Cynthia M. Powell
Keyword(s):  
Chromosome Rearrangements ◽  
Complex Chromosome

scholarly journals Unprecedented reorganization of holocentric chromosomes provides insights into the enigma of lepidopteran chromosome evolution

2019 ◽  
Vol 5 (6) ◽  
pp. eaau3648 ◽  
Author(s):  
Jason Hill ◽  
Pasi Rastas ◽  
Emily A. Hornett ◽  
Ramprasad Neethiraj ◽  
Nathan Clark ◽  
...  
Keyword(s):  
Chromosome Number ◽  
Chromosome Evolution ◽  
Chromosome Structure ◽  
Holocentric Chromosomes ◽  
Chromosome Counts ◽  
Pieris Napi ◽  
Haploid Chromosome Number ◽  
Genome Wide ◽  
The Face ◽  
Chromosome Level

Chromosome evolution presents an enigma in the mega-diverse Lepidoptera. Most species exhibit constrained chromosome evolution with nearly identical haploid chromosome counts and chromosome-level gene collinearity among species more than 140 million years divergent. However, a few species possess radically inflated chromosomal counts due to extensive fission and fusion events. To address this enigma of constraint in the face of an exceptional ability to change, we investigated an unprecedented reorganization of the standard lepidopteran chromosome structure in the green-veined white butterfly (Pieris napi). We find that gene content in P. napi has been extensively rearranged in large collinear blocks, which until now have been masked by a haploid chromosome number close to the lepidopteran average. We observe that ancient chromosome ends have been maintained and collinear blocks are enriched for functionally related genes suggesting both a mechanism and a possible role for selection in determining the boundaries of these genome-wide rearrangements.

scholarly journals ATRAID regulates the action of nitrogen-containing bisphosphonates on bone

2020 ◽  
Vol 12 (544) ◽  
pp. eaav9166 ◽  
Author(s):  
Lauren E. Surface ◽  
Damon T. Burrow ◽  
Jinmei Li ◽  
Jiwoong Park ◽  
Sandeep Kumar ◽  
...  
Keyword(s):  
Osteonecrosis Of The Jaw ◽  
Pharmacological Effects ◽  
Protein Prenylation ◽  
Genome Wide ◽  
Cellular Factors ◽  
Osteoclast Function ◽  
Differential Responsiveness ◽  
Coding Variants ◽  
Deficient Mice ◽  
Insight Into

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP–mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.

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