Mystery at the heart of life

_{Denyse O'Leary

December 21, 2014

Cell biology, Intelligent Design, News}

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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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Comments

[...] both an in-depth biochemical analysis of Lte1 and further examination of how Lte1’s GEF domains activate the MEN are critical to elucidate the function of Lte1. [...] an additional layer of control, the so-called spindle position checkpoint, becomes important. This regulatory mechanism buys the cell time during anaphase so that it can thread the anaphase spindle into the bud.
LTE1 promotes exit from mitosis by multiple mechanisms Jill E. Falk, Ian W. Campbell, Kelsey Joyce, Jenna Whalen, Anupama Seshan, and Angelika Amon Mol Biol Cell. 27(25): 3991–4001. doi: 10.1091/mbc.E16-08-0563

An additional layer of control? Another one? A regulatory mechanism that buys time purposely? Huh? Complex complexity.Dionisio_{May 15, 2017
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Polarized cell division is a defining characteristic of development and one mechanism by which cells produce progeny with distinct cell fates [...] Because these asymmetric cell divisions rely on the unequal distribution of fate determinants within the cell, it is critical that the mitotic spindle and hence the plane of cell division are correctly placed with respect to these spatially restricted developmental cues. Evidence suggests that feedback mechanisms that sense spindle position are in place to ensure that this occurs. [...] control of the MEN [mitotic exit network] by spindle position is exerted by both negative and positive regulatory elements that control the pathway’s GTPase activity.
LTE1 promotes exit from mitosis by multiple mechanisms Jill E. Falk, Ian W. Campbell, Kelsey Joyce, Jenna Whalen, Anupama Seshan, and Angelika Amon Mol Biol Cell. 27(25): 3991–4001. doi: 10.1091/mbc.E16-08-0563

How did we get those "sensing feedback mechanisms" to begin with? Complex complexity.Dionisio_{May 15, 2017
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[...] local satisfaction of checkpoints seems to be sufficient for global checkpoint silencing in binucleated cells. [...] misbalanced checkpoint integrity in binucleated cells might be a driver for genome instability and cancer development.
A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Had we stayed in Eden none of this would have been an issue. Like Sinatra, we preferred to do things our way. Too late now. Human history is messed up. The good news is that the ultimate remedy for the malady has been revealed and graciously offered to all. Now it's up to each of us to accept it and enjoy it. Complex complexity.Dionisio_{May 15, 2017
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[...] cell polarity associated factors play a critical role in SPOC silencing and mitotic exit [...] The molecular characterization of these factors, which were undermined in the last decade, will be critical to shed light onto the mechanisms controlling mitotic exit and/or SPOC silencing.
A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Work in progress... stay tuned. Complex complexity.Dionisio_{May 15, 2017
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[...] cells do not require an intact cytoplasmic microtubule cytoskeleton to establish and/or maintain Bfa1-Bub2 asymmetry. How cell polarity determinants control Bfa1 asymmetry is unclear.
A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity.Dionisio_{May 15, 2017
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The Bfa1-Bub2 complex is recruited preferentially to the dSPB (asymmetric binding) in cells progressing normally through the cell cycle. How this asymmetry is established is still unclear.
A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

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[...] Spc72 acts as a scaffold protein that coordinates the regulation of the checkpoint effector Bfa1 by both Kin4 and Cdc5 kinases in cells with mis-aligned spindle. [...] further biochemical and biophysical studies will be necessary to evaluate the affinity of Bfa1 towards Nud1 and Spc72, and to establish whether the same Bfa1 molecule can bind simultaneously to Nud1 and Spc72.
A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity.Dionisio_{May 15, 2017
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Spindle pole bodies (SPBs) not only facilitate microtubule nucleation but also provide a scaffolding platform for binding of the mitotic exit network (MEN) and the spindle position checkpoint (SPOC) proteins. Our findings unraveled a novel molecular rearrangement of SPOC proteins at SPBs that is essential for SPOC function. [...] the SPOC is switched off as soon as one spindle enters the bud.
A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity.Dionisio_{May 15, 2017
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A cell must duplicate its genetic material and then separate the two copies before it divides. This process is carefully controlled so that each new cell receives an identical set of chromosomes after cell division. The spindle position checkpoint (SPOC) is a spindle pole body (SPB, equivalent of mammalian centrosome) associated surveillance mechanism that halts mitotic exit upon spindle mis-orientation.
A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity.Dionisio_{May 15, 2017
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Whether the cell requires an intelligent sensor to detect spindle orientation defects, or solely relies on compartmentalization for the SPOC function remains to be clarified.
Temporal and compartment-specific signals coordinate mitotic exit with spindle position Ayse Koca Caydasi, Anton Khmelinskii, Rafael Duenas-Sanchez, Bahtiyar Kurtulmus, Michael Knop and Gislene Pereiraa Nat Commun. 8: 14129. doi: 10.1038/ncomms14129

Did somebody say "intelligent"? Complex complexity.Dionisio_{May 14, 2017
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[...] FEAR, MEN, SPOC and daughter cell-associated factors regulate mitotic exit in space and time through an intricate combination of independent pathways that apply control at the level of compartmentalization (Lte1, Ste20) and timing (FEAR).
Temporal and compartment-specific signals coordinate mitotic exit with spindle position Ayse Koca Caydasi, Anton Khmelinskii, Rafael Duenas-Sanchez, Bahtiyar Kurtulmus, Michael Knop and Gislene Pereiraa Nat Commun. 8: 14129. doi: 10.1038/ncomms14129

Did somebody say "regulate"? Did somebody say "control"? Complex complexity.Dionisio_{May 14, 2017
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@3367: Did somebody say "orchestrate"? :)Dionisio_{May 14, 2017
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[...] a comprehensive understanding of how cells decide when to exit mitosis is still lacking.
Temporal and compartment-specific signals coordinate mitotic exit with spindle position Ayse Koca Caydasi, Anton Khmelinskii, Rafael Duenas-Sanchez, Bahtiyar Kurtulmus, Michael Knop and Gislene Pereiraa Nat Commun. 8: 14129. doi: 10.1038/ncomms14129

Did somebody say that "cells decide"? Complex complexity.Dionisio_{May 14, 2017
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The spatiotemporal control of mitotic exit is crucial for faithful chromosome segregation during mitosis. How the SPOC operates at a molecular level remains unclear. [...] mitotic signalling pathways orchestrate chromosome segregation in time and space.
Temporal and compartment-specific signals coordinate mitotic exit with spindle position Ayse Koca Caydasi, Anton Khmelinskii, Rafael Duenas-Sanchez, Bahtiyar Kurtulmus, Michael Knop and Gislene Pereiraa Nat Commun. 8: 14129. doi: 10.1038/ncomms14129

Complex complexity.Dionisio_{May 14, 2017
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Further investigation is needed to better understand the molecular basis and importance of these cell-to-cell differences. The analysis of cells with multiple centrosomes analogous to what has been described here could address this question.
Spatial signals link exit from mitosis to spindle position Jill Elaine Falk, Dai Tsuchiya, Jolien Verdaasdonk, Soni Lacefield, Kerry Bloom, and Angelika Amon eLife. 5: e14036. doi: 10.7554/eLife.14036

Complex complexity.Dionisio_{May 14, 2017
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Asymmetric cell division is a common characteristic of development and is seen in diverse cell types ranging from Drosophila neuroblasts to mammalian oocytes. In order to produce viable progeny with distinct cell fates, asymmetrically dividing cells must coordinate nuclear position with the site of cytokinesis.
Spatial signals link exit from mitosis to spindle position Jill Elaine Falk, Dai Tsuchiya, Jolien Verdaasdonk, Soni Lacefield, Kerry Bloom, and Angelika Amon eLife. 5: e14036. doi: 10.7554/eLife.14036

Did somebody say "coordinate"? Complex complexity.Dionisio_{May 14, 2017
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[...] exit from mitosis is triggered by a correctly positioned spindle rather than inhibited by improper spindle position.
Spatial signals link exit from mitosis to spindle position Jill Elaine Falk, Dai Tsuchiya, Jolien Verdaasdonk, Soni Lacefield, Kerry Bloom, and Angelika Amon eLife. 5: e14036. doi: 10.7554/eLife.14036

Complex complexity.Dionisio_{May 14, 2017
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Stem cells are characterized by their ability to asymmetrically divide, generating another self-renewing stem cell and a differentiating daughter cell. They reside within the local niche microenvironment, which, together with systemic signals, regulates intrinsic stem cell function. Stem cells are finely regulated [...] Despite what is already known, much remains to be studied about how systemic, extrinsic, and intrinsic factors coordinate to regulate stem cell function. [...] many questions still remain unanswered.
Regulation of Stem Cells in Their Niche Li Ming Gooi & Jay Gopalakrishnan Curr Stem Cell Rep 2:282–289 DOI 10.1007/s40778-016-0048-2

Complex complexity.Dionisio_{May 14, 2017
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During mitosis, cells must accurately segregate their genome in order to produce healthy daughter cells. While the molecular functions of Kin4 and Tem1 are well defined, the function of Ltel has remained unclear.
Mechanisms underlying spatial control of exit from mitosis Jill E Falk MIT Thesis

Complex complexity.Dionisio_{May 14, 2017
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How the information on centrosomal orientation is communicated to the spectrosome, where Par-1 and Cyclin A localize, remains to be determined. A major outstanding question in understanding the COC is how it senses the location of the centrosomewith respect to the hub cells. It awaits future investigation to understand how the association of the centrosome with the hub-GSC interface is mechanistically sensed, and how such information is integrated with the activity of COC component(s) on the spectrosome. [...] the COC is a checkpoint mechanism that is distinct from the SAC and monitors correct centrosome orientation specifically in GSCs. We speculate that a similar mechanism might be in place in other systems that rely on asymmetric cell division.
The centrosome orientation checkpoint is germline stem cell specific and operates prior to the spindle assembly checkpoint in Drosophila testis Zsolt G. Venkei and Yukiko M. Yamashita DOI: 10.1242/dev.117044 Development

Note that this paper was previously referenced @112 & @164 but both quoted mainly the abstract while this new reference quotes the conclusions. This paper is old in practical terms, but perhaps still at least partially valid. Perhaps some of the outstanding questions in this paper have been resolved since it got published. Complex complexity.Dionisio_{May 14, 2017
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Neuroblasts are neural stem cells that divide asymmetrically to produce one self-renewing neuroblast and one daughter cell that divides once more to generate two neurons or glial cells. Asymmetric inheritance of determinants of cell fate requires the apically localized protein Partner of Inscuteable (Pins), which interacts with the Par complex through the adaptor protein Inscuteable (Insc). Pins also interacts with Discs large (Dlg) and Mushroom body defect (Mud), both of which also interact with the spindle pole. Thus, Pins orients cell divisions by ensuring that one spindle pole localizes to the apical side of the neuroblast. [...] Hippo signaling influences spindle orientation through the Wts-mediated phosphorylation of the Pins-interacting proteins Cno and Mud.
Hippo signaling for spindle orientation Annalisa M. VanHook Sci. Signal. Vol. 8, Issue 402, pp. ec331 DOI: 10.1126/scisignal.aad8102

Complex complexity.Dionisio_{May 14, 2017
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Stem cells possess the extraordinary capacity of self-renewal and differentiation to various cell types, thus to form original tissues and organs. Stem cell heterogeneity including genetic and nongenetic mechanisms refers to biological differences amongst normal and stem cells originated within the same tissue. Cell differentiation hierarchy and stochasticity in gene expression and signaling pathways may result in phenotypic differences of stem cells. The maintenance of stemness and activation of differentiation potential are fundamentally orchestrated by microenvironmental stem cell niche-related cellular and humoral signals.
Heterogeneity of Stem Cells: A Brief Overview. M?zes G, Sipos F Methods Mol Biol. 1516:1-12. doi: 10.1007/7651_2016_345.

Did somebody say "orchestrated"? Complex complexity.Dionisio_{May 14, 2017
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[...] the origin of adult stem cells in some mature tissues is still to be elucidated. The big hurdle is the fact that the tissue microenvironment is very complex and reproducing the in vivo conditions required for stem cell differentiation is very difficult.
Adult Stem Cell Responses to Nanostimuli Penelope M. Tsimbouri Journal of Functional Biomaterials 6, 598-622; doi:10.3390/jfb6030598 http://www.mdpi.com/journal/jfb

Complex complexity.Dionisio_{May 14, 2017
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Adult or mesenchymal stem cells (MSCs) have been found in different tissues in the body, residing in stem cell microenvironments called “stem cell niches”. They play different roles but their main activity is to maintain tissue homeostasis and repair throughout the lifetime of an organism. Their ability to differentiate into different cell types makes them an ideal tool to study tissue development and to use them in cell-based therapies. This differentiation process is subject to both internal and external forces at the nanoscale level [...]
Adult Stem Cell Responses to Nanostimuli Penelope M. Tsimbouri Journal of Functional Biomaterials 6, 598-622; doi:10.3390/jfb6030598 www.mdpi.com/journal/jfb

Complex complexity.Dionisio_{May 14, 2017
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The human cerebral cortex is dramatically larger compared with that of other mammals [...] [...] the role of these proteins [that localize to the mitotic spindle poles] in the interphase centrosome is not clear. The centrosome consists of a pair of centrioles surrounded by pericentriolar material, which nucleates microtubules that allow the centrosome to serve as the major microtubule-organizing center in mammalian cells [...]
Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate Divya Jayaraman, Andrew Kodani, Dilenny M. Gonzalez, Joseph D. Mancias, Ganeshwaran H. Mochida, Cristiana Vagnoni, Jeffrey Johnson, Nevan Krogan, J. Wade Harper, Jeremy F. Reiter, Timothy W. Yu, Byoung-il Bae and Christopher A. Walsh DOI: 10.1016/j.neuron.2016.09.056 Neuron 92, 1–16

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The role of the MR in cell fate specification remains elusive [...] [...] the biological significance of asymmetric MR inheritance is not well understood beyond correlative relationships [...]
Evaluation of the Asymmetric Division of Drosophila Male Germline Stem Cells Mayu Inaba and Yukiko M. Yamashita DOI: 10.1007/978-1-4939-4017-2_3 Germline Stem Cells, Methods in Molecular Biology, vol. 1463,

Complex complexity.Dionisio_{May 11, 2017
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These studies suggest the presence of intricate mechanisms to asymmetrically segregate cellular components, possibly contributing to ACD. Yet, such asymmetries associated with ACD have only begun to be revealed and it remains unclear how critical these asymmetries are in determining asymmetric cell fates.
Evaluation of the Asymmetric Division of Drosophila Male Germline Stem Cells Mayu Inaba and Yukiko M. Yamashita DOI: 10.1007/978-1-4939-4017-2_3 Germline Stem Cells, Methods in Molecular Biology, vol. 1463,

Complex complexity.Dionisio_{May 11, 2017
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Asymmetric cell division (ACD) is utilized in many stem cell systems to produce two daughter cells with different cell fates. Despite the fundamental importance of ACD during development and tissue homeostasis, the nature of ACD is far from being fully understood. Step-by-step observation of events during ACD allows us to understand processes that lead to ACD.
Evaluation of the Asymmetric Division of Drosophila Male Germline Stem Cells Mayu Inaba and Yukiko M. Yamashita DOI: 10.1007/978-1-4939-4017-2_3 Germline Stem Cells, Methods in Molecular Biology, vol. 1463,

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[...] ACD is achieved by fine-tuned symmetries and asymmetries [...] [...] multiple aspects of ACDs (e.g. asymmetric segregation of fate determinants, spindle orientation, daughter cell size asymmetry) are carefully calibrated processes to achieve successful ACD unique to individual systems.
Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division Cuie Chen, Mayu Inaba, Zsolt G Venkei, Yukiko M Yamashita DOI: 10.7554/eLife.04960 eLife Sciences

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Asymmetric cell division (ACD) is a key process that balances stem cell self-renewal and differentiation by producing one stem cell and one differentiating cell [...] [...] the essence of successful cell division is the precise replication and segregation of cellular contents, such as chromosomes and essential organelles. It has been underexplored how cells may achieve productive ACD without interfering with the basic requirement of cell divisions.
Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division Cuie Chen, Mayu Inaba, Zsolt G Venkei, Yukiko M Yamashita DOI: 10.7554/eLife.04960 eLife Sciences

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