scholarly journals Micronuclei-based model system reveals functional consequences of chromothripsis in human cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Maja Kneissig ◽  
Kristina Keuper ◽  
Mirjam S de Pagter ◽  
Markus J van Roosmalen ◽  
Jana Martin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromosomal Aberrations ◽  
Extra Chromosome ◽  
Chromosomal Rearrangements ◽  
Model System ◽  
Membrane Curvature ◽  
Human Cells ◽  
Model Systems ◽  
Lamin B1 ◽  
Functional Consequences

Cancer cells often harbor chromosomes in abnormal numbers and with aberrant structure. The consequences of these chromosomal aberrations are difficult to study in cancer, and therefore several model systems have been developed in recent years. We show that human cells with extra chromosome engineered via microcell-mediated chromosome transfer often gain massive chromosomal rearrangements. The rearrangements arose by chromosome shattering and rejoining as well as by replication-dependent mechanisms. We show that the isolated micronuclei lack functional lamin B1 and become prone to envelope rupture, which leads to DNA damage and aberrant replication. The presence of functional lamin B1 partly correlates with micronuclei size, suggesting that the proper assembly of nuclear envelope might be sensitive to membrane curvature. The chromosomal rearrangements in trisomic cells provide growth advantage compared to cells without rearrangements. Our model system enables to study mechanisms of massive chromosomal rearrangements of any chromosome and their consequences in human cells.

scholarly journals Engineering chromosome rearrangements in cancer

2021 ◽  
Vol 14 (9) ◽  
Author(s):  
Salvador Alonso ◽  
Lukas E. Dow
Keyword(s):  
Genome Editing ◽  
Chromosomal Aberrations ◽  
Chromosomal Rearrangements ◽  
Therapeutic Strategies ◽  
Chromosome Rearrangements ◽  
Model Systems ◽  
Cancer Growth ◽  
Clinical Models

ABSTRACT The identification of large chromosomal rearrangements in cancers has multiplied exponentially over the last decade. These complex and often rare genomic events have traditionally been challenging to study, in part owing to lack of tools that efficiently engineer disease-associated inversions, deletions and translocations in model systems. The emergence and refinement of genome editing technologies, such as CRISPR, have significantly expanded our ability to generate and interrogate chromosomal aberrations to better understand the networks that govern cancer growth. Here we review how existing technologies are employed to faithfully model cancer-associated chromosome rearrangements in the laboratory, with the ultimate goal of developing more accurate pre-clinical models of and therapeutic strategies for cancers driven by these genomic events.

scholarly journals Author response: Micronuclei-based model system reveals functional consequences of chromothripsis in human cells

2019 ◽  
Author(s):  
Maja Kneissig ◽  
Kristina Keuper ◽  
Mirjam S de Pagter ◽  
Markus J van Roosmalen ◽  
Jana Martin ◽  
...  
Keyword(s):  
Model System ◽  
Human Cells ◽  
Author Response ◽  
Functional Consequences

scholarly journals Singularly Perturbed Oscillators with Exponential Nonlinearities

2021 ◽  
Author(s):  
S. Jelbart ◽  
K. U. Kristiansen ◽  
P. Szmolyan ◽  
M. Wechselberger
Keyword(s):  
Limit Cycles ◽  
Space Dimension ◽  
Blow Up ◽  
Exponential Convergence ◽  
Model System ◽  
Piecewise Smooth ◽  
Singularly Perturbed ◽  
Model Systems ◽  
Smooth System ◽  
Unique Limit

AbstractSingular exponential nonlinearities of the form $$e^{h(x)\epsilon ^{-1}}$$ e h ( x ) ϵ - 1 with $$\epsilon >0$$ ϵ > 0 small occur in many different applications. These terms have essential singularities for $$\epsilon =0$$ ϵ = 0 leading to very different behaviour depending on the sign of h. In this paper, we consider two prototypical singularly perturbed oscillators with such exponential nonlinearities. We apply a suitable normalization for both systems such that the $$\epsilon \rightarrow 0$$ ϵ → 0 limit is a piecewise smooth system. The convergence to this nonsmooth system is exponential due to the nonlinearities we study. By working on the two model systems we use a blow-up approach to demonstrate that this exponential convergence can be harmless in some cases while in other scenarios it can lead to further degeneracies. For our second model system, we deal with such degeneracies due to exponentially small terms by extending the space dimension, following the approach in Kristiansen (Nonlinearity 30(5): 2138–2184, 2017), and prove—for both systems—existence of (unique) limit cycles by perturbing away from singular cycles having desirable hyperbolicity properties.

scholarly journals NEIL2 Protects against Oxidative DNA Damage Induced by Sidestream Smoke in Human Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. e90261 ◽  
Author(s):  
Altaf H. Sarker ◽  
Arpita Chatterjee ◽  
Monique Williams ◽  
Sabrina Lin ◽  
Christopher Havel ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Human Cells ◽  
Sidestream Smoke

scholarly journals Paracoccus denitrificans: a genetically tractable model system for studying respiratory complex I

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Owen D. Jarman ◽  
Olivier Biner ◽  
John J. Wright ◽  
Judy Hirst
Keyword(s):  
Complex I ◽  
Paracoccus Denitrificans ◽  
Model System ◽  
Proton Pumping ◽  
Model Systems ◽  
Metabolic Enzyme ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Inner Mitochondrial Membrane

AbstractMitochondrial complex I (NADH:ubiquinone oxidoreductase) is a crucial metabolic enzyme that couples the free energy released from NADH oxidation and ubiquinone reduction to the translocation of four protons across the inner mitochondrial membrane, creating the proton motive force for ATP synthesis. The mechanism by which the energy is captured, and the mechanism and pathways of proton pumping, remain elusive despite recent advances in structural knowledge. Progress has been limited by a lack of model systems able to combine functional and structural analyses with targeted mutagenic interrogation throughout the entire complex. Here, we develop and present the α-proteobacterium Paracoccus denitrificans as a suitable bacterial model system for mitochondrial complex I. First, we develop a robust purification protocol to isolate highly active complex I by introducing a His6-tag on the Nqo5 subunit. Then, we optimize the reconstitution of the enzyme into liposomes, demonstrating its proton pumping activity. Finally, we develop a strain of P. denitrificans that is amenable to complex I mutagenesis and create a catalytically inactive variant of the enzyme. Our model provides new opportunities to disentangle the mechanism of complex I by combining mutagenesis in every subunit with established interrogative biophysical measurements on both the soluble and membrane bound enzymes.

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