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The “beautiful mechanism” by which an egg becomes an embryo

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From Phys.org:

The transition from an egg to a developing embryo is one of life’s most remarkable transformations. Yet little is known about it. Now Whitehead Institute researchers have deciphered how one aspect—control of the all-important translation of messenger RNAs (mRNAs) into proteins—switches as the egg becomes an embryo. That shift is controlled by a beautiful mechanism, which is triggered at a precise moment in development and automatically shuts itself off after a narrow window of 20 to 90 minutes.

As an egg develops, it stockpiles mRNAs from the mother because it will not have time to create new mRNAs during the rapid development of a very early embryo. When fertilized the egg becomes an embryo, the stashed maternal mRNAs are pressed into service for a brief window before the embryo starts transcribing its own mRNAs. This change occurs very early; in humans, only two to four cell divisions occur before this transition is executed. Whitehead Member Terry Orr-Weaver studies the control of translation of maternal mRNAs in the model organism Drosophila, or the fruit fly, because its developmental strategy offers experimental advantages. More.

A reader writes to note that the “beautiful mechanism” is described as a

negative feedback loop,” with the same function as those designed in engineering control systems: Furthermore, the activity of PNG kinase leads to the destruction of GNU, and this feedback loop limits this kinase’s activity to the narrow window of time in which it is needed.

“Active PNG leads to decreased GNU protein levels. This makes a negative feedback to shut down PNG kinase activity, thereby ensuring PNG kinase activity is constrained to the short developmental window of the oocyte-to-embryo transition

Another reader who forwarded this item points out that the authors let in the “d” word (and I don’t mean “Darwin”…. ):

The design of this transition could tell scientists more about how human cells work and embryos develop. For example, the switch could be a model for how cells massively and globally change mRNA translation. Also, similar kinase activity during early development has been noted in worms, which may mean that a comparable approach is used in other organisms, including humans.

Well, if the researchers’ careers take a beating for mentioning design, they will need to join the Free the Universities movement. After a while language Stalinism starts t collapse from its own uncommunicativeness and one must peak clearly again.

See also: Cells communicate to navigate a crowded embryo

Comments
These findings establish novel regulatory mechanisms, which prevent concurrent detachment of telomeres and centromeres from the SPB during bouquet formation and secure proper meiotic divisions. Our findings reveal a hitherto unknown regulatory relationship between meiotic telomere and centromere positions in bouquet formation, which secures proper meiotic divisions.
A Taz1- and Microtubule-Dependent Regulatory Relationship between Telomere and Centromere Positions in Bouquet Formation Secures Proper Meiotic Divisions. Katsumata K1, Hirayasu A1, Miyoshi J2, Nishi E1, Ichikawa K1, Tateho K1, Wakuda A2, Matsuhara H3, Yamamoto A PLoS Genet. 12(9):e1006304. doi: 10.1371/journal.pgen.1006304.
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During meiotic prophase, telomeres cluster, forming the bouquet chromosome arrangement, and facilitate homologous chromosome pairing. In fission yeast, bouquet formation requires switching of telomere and centromere positions. Centromeres are located at the spindle pole body (SPB) during mitotic interphase, and upon entering meiosis, telomeres cluster at the SPB, followed by centromere detachment from the SPB. Telomere clustering depends on the formation of the microtubule-organizing center at telomeres by the linker of nucleoskeleton and cytoskeleton complex (LINC), while centromere detachment depends on disassembly of kinetochores, which induces meiotic centromere formation. However, how the switching of telomere and centromere positions occurs during bouquet formation is not fully understood.
A Taz1- and Microtubule-Dependent Regulatory Relationship between Telomere and Centromere Positions in Bouquet Formation Secures Proper Meiotic Divisions. Katsumata K1, Hirayasu A1, Miyoshi J2, Nishi E1, Ichikawa K1, Tateho K1, Wakuda A2, Matsuhara H3, Yamamoto A PLoS Genet. 12(9):e1006304. doi: 10.1371/journal.pgen.1006304.
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In meiosis I, chromosomes become paired with their homologous partners and then are pulled toward opposite poles of the spindle. In the budding yeast, Saccharomyces cerevisiae, in early meiotic prophase, centromeres are observed to associate in pairs in a homology-independent manner; a process called centromere coupling. Later, as homologous chromosomes align, their centromeres associate in a process called centromere pairing. The synaptonemal complex protein Zip1 is necessary for both types of centromere association. [...] centromere pairing, which was previously shown to be necessary to ensure disjunction of achiasmate chromosomes, is not sufficient for ensuring their disjunction.
Meiotic Centromere Coupling and Pairing Function by Two Separate Mechanisms in Saccharomyces cerevisiae. Kurdzo EL, Obeso D, Chuong H, Dawson DS Genetics. 205(2):657-671. doi: 10.1534/genetics.116.190264
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The role of centromere coupling remains unknown. Identification of additional functional requirements for centromere coupling will likely provide more clues into its role in early meiosis.
Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern. Lefrançois P, Rockmill B, Xie P, Roeder GS, Snyder M PLoS Genet. 12(10):e1006347. doi: 10.1371/journal.pgen.1006347.
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Processes in meiosis are geared to recombine homologous chromosomes to both increase genetic diversity, and segregate them efficiently thus producing viable gametes for sexual reproduction. Homologous pairing and recombination between chromosomes favor the formation of stable pairs [2, 3], which are secured by the proteinaceous synaptonemal complex (SC), containing ZMM proteins such as Zip1 [4]. Two dynamic homology-independent events precede homolog pairing: the meiotic bouquet and non-homologous centromere coupling. [...] centromere coupling, with its preference for chromosomes of similar size, helps chromosomes find their homolog.
Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern. Lefrançois P, Rockmill B, Xie P, Roeder GS, Snyder M PLoS Genet. 12(10):e1006347. doi: 10.1371/journal.pgen.1006347.
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[...] a chromosome size preference for centromere coupling helps establish efficient homolog recognition. Meiosis enables sexual reproduction in eukaryotes by producing gametes. In the process, it increases genetic diversity through recombination of homologous chromosomes from the parents. Prior to finding their unique pairing partner (homolog), chromosomes associate non-homologously with other chromosomes through their centromeres, a process termed centromere coupling. Little is known about the nature and mechanism of centromere coupling.
Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern. Lefrançois P, Rockmill B, Xie P, Roeder GS, Snyder M PLoS Genet. 12(10):e1006347. doi: 10.1371/journal.pgen.1006347.
Reshuffling existing genetic/epigenetic information? Embedded Variability Framework (EVF)? Complex functionally specified informational complexityDionisio
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During meiosis, chromosomes undergo a homology search in order to locate their homolog to form stable pairs and exchange genetic material. Early in prophase, chromosomes associate in mostly non-homologous pairs, tethered only at their centromeres. This phenomenon, conserved through higher eukaryotes, is termed centromere coupling in budding yeast. Both initiation of recombination and the presence of homologs are dispensable for centromere coupling (occurring in spo11 mutants and haploids induced to undergo meiosis) but the presence of the synaptonemal complex (SC) protein Zip1 is required. The nature and mechanism of coupling have yet to be elucidated.
Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern. Lefrançois P, Rockmill B, Xie P, Roeder GS, Snyder M PLoS Genet. 12(10):e1006347. doi: 10.1371/journal.pgen.1006347.
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Faithful genome propagation requires coordination between nuclear envelope (NE) breakdown, spindle formation, and chromosomal events. [...] interphase chromosome-LINC contacts constitute a cell-cycle control device linking nucleoplasmic and cytoplasmic events.
Mitotic Nuclear Envelope Breakdown and Spindle Nucleation Are Controlled by Interphase Contacts between Centromeres and the Nuclear Envelope. Fernández-Álvarez A1, Bez C2, O'Toole ET3, Morphew M3, Cooper JP4 Dev Cell. 39(5):544-559. doi: 10.1016/j.devcel.2016.10.021
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We anticipate that our in vitro mechanical approach to studying SPB–microtubule attachments will allow further dissection of the molecular basis for their very high strength. Our work should also guide efforts to study the centrosomes of other eukaryotes and facilitate direct tests for whether forces control phosphoregulation or other signaling events at SPBs.
Direct measurement of the strength of microtubule attachment to yeast centrosomes. Fong KK1, Sarangapani KK2, Yusko EC2, Riffle M1, Llauró A2, Graczyk B1, Davis TN1, Asbury CL Mol Biol Cell. 28(14):1853-1861. doi: 10.1091/mbc.E17-01-0034
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The strength of SPB–microtubule attachment is very high, exceeding the strength of attachment between kinetochores and growing microtubule plus ends by approximately fourfold. [...] this strong anchorage to SPBs might be important for spindle integrity in mitotic cells [...] [...] microtubule attachment strength depends on the tethering molecule, Spc110, and calmodulin. [...] these mammalian proteins might also contribute mechanical strength to minus-end attachments at mammalian centrosomes.
Direct measurement of the strength of microtubule attachment to yeast centrosomes. Fong KK1, Sarangapani KK2, Yusko EC2, Riffle M1, Llauró A2, Graczyk B1, Davis TN1, Asbury CL Mol Biol Cell. 28(14):1853-1861. doi: 10.1091/mbc.E17-01-0034
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The centrosome is the microtubule-organizing center of the cell, responsible for nucleation of microtubules and organization of the bipolar mitotic spindle. Centrosomes serve as mechanical hubs, subjected to force from interpolar microtubules [...], kinetochore microtubules [...], and astral microtubules [...] [...] the mechanical strength of centrosome–microtubule attachments is unknown, and the role of mechanical signals at centrosomes remains unclear. The complexity and dynamics of pericentriolar material make it difficult to understand how forces are transmitted through the mammalian centrosome structure.
Direct measurement of the strength of microtubule attachment to yeast centrosomes. Fong KK1, Sarangapani KK2, Yusko EC2, Riffle M1, Llauró A2, Graczyk B1, Davis TN1, Asbury CL Mol Biol Cell. 28(14):1853-1861. doi: 10.1091/mbc.E17-01-0034
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Centrosomes, or spindle pole bodies (SPBs) in yeast, are vital mechanical hubs that maintain load-bearing attachments to microtubules during mitotic spindle assembly, spindle positioning, and chromosome segregation. However, the strength of microtubule-centrosome attachments is unknown, and the possibility that mechanical force might regulate centrosome function has scarcely been explored. [...] calmodulin binding contributes to SPB mechanical integrity [...] [...] the very high strength of SPB-microtubule attachments may be important for spindle integrity in mitotic cells so that tensile forces generated at kinetochores do not cause microtubule detachment and delamination at SPBs.
Direct measurement of the strength of microtubule attachment to yeast centrosomes. Fong KK1, Sarangapani KK2, Yusko EC2, Riffle M1, Llauró A2, Graczyk B1, Davis TN1, Asbury CL Mol Biol Cell. 28(14):1853-1861. doi: 10.1091/mbc.E17-01-0034
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[...] the bridge structure that separates the mSPB from the satellite is a distance holder that prevents deleterious fusion of both structures. Binding of the ?-tubulin receptor Spc110 to the central plaque from within the nucleus is important for NE insertion of the new SPB. [...] a nuclear pore complex associates with the duplicating SPB and helps to insert the SPB into the NE. After SPB insertion, membrane-associated proteins including the conserved Ndc1 encircle the SPB and retain it within the NE. Thus, uncoupling SPB growth from NE insertion unmasks functions of the duplication machinery.
Characterization of spindle pole body duplication reveals a regulatory role for nuclear pore complexes. Rüthnick D1, Neuner A1, Dietrich F1, Kirrmaier D1, Engel U2, Knop M1, Schiebel E3. J Cell Biol. 216(8):2425-2442. doi: 10.1083/jcb.201612129
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The spindle pole body (SPB) of budding yeast duplicates once per cell cycle. In G1, the satellite, an SPB precursor, assembles next to the mother SPB (mSPB) on the cytoplasmic side of the nuclear envelope (NE). How the growing satellite subsequently inserts into the NE is an open question.
Characterization of spindle pole body duplication reveals a regulatory role for nuclear pore complexes. Rüthnick D1, Neuner A1, Dietrich F1, Kirrmaier D1, Engel U2, Knop M1, Schiebel E3. J Cell Biol. 216(8):2425-2442. doi: 10.1083/jcb.201612129
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[...] further studies will reveal similar networks in mitotic controls in other systems as both CK1? and Chk2 are recruited to human centrosomes [...] [...] it remains to be established whether it is this centrosomal pool of CK1? that mediates these controls. Such extensive similarities between fission yeast and human centrosomal CK1?/Chk2/Aurora A/Polo signaling define some simple dependency relationships that can be probed in higher systems to unravel the complex usage of the spindle pole as a hub at which to coordinate signaling events that determine cell fate.
Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment. Chan KY1, Alonso-Nuñez M2, Grallert A2, Tanaka K2, Connolly Y3, Smith DL3, Hagan IM4. J Cell Biol. 216(9):2795-2812. doi: 10.1083/jcb.201702172.
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This dialog between two independent scaffolds reinforces the robustness of the mitotic switch. The concept of dialog between scaffolding proteins on the SPB addresses the longstanding question as to why mitotic entry and exit should be regulated from the spindle pole. Centrosomal scaffold dialog can integrate inputs from diverse signaling networks with a limited number of neighboring molecules in order to generate a single coherent output that can then be amplified throughout the cell. Alongside centrosomal signaling in cell cycle and DNA checkpoint controls, the overriding impact of the spindle assembly checkpoint signal emanating from a single kinetochore provides another example of the dramatic impact that coordinated singling from a single center can have [...]
Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment. Chan KY1, Alonso-Nuñez M2, Grallert A2, Tanaka K2, Connolly Y3, Smith DL3, Hagan IM4. J Cell Biol. 216(9):2795-2812. doi: 10.1083/jcb.201702172.
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In some systems, engagement of Polo feedback control influences the rate of mitotic commitment, whereas in others, Polo activity sets its timing [...] [...] the incorporation of the DNA replication checkpoint kinase Chk2Cds1 offers further potential for signals emanating from Sid4 to integrate inputs from replication/repair pathways into cell cycle control as reported for DNA checkpoint control by human centrosome components [...]
Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment. Chan KY1, Alonso-Nuñez M2, Grallert A2, Tanaka K2, Connolly Y3, Smith DL3, Hagan IM4. J Cell Biol. 216(9):2795-2812. doi: 10.1083/jcb.201702172.
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The fission yeast scaffold molecule Sid4 anchors the septum initiation network to the spindle pole body (SPB, centrosome equivalent) to control mitotic exit events. A second SPB-associated scaffold, Cut12, promotes SPB-associated Cdk1–cyclin B to drive mitotic commitment. [...] signals from Sid4 contribute to the Cut12 mitotic commitment switch. Such integration of signals emanating from neighboring scaffolds shows how centrosomes/SPBs can integrate inputs from multiple pathways to control cell fate.
Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment. Chan KY1, Alonso-Nuñez M2, Grallert A2, Tanaka K2, Connolly Y3, Smith DL3, Hagan IM4. J Cell Biol. 216(9):2795-2812. doi: 10.1083/jcb.201702172.
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Microtubule-organizing centers (MTOCs), known as centrosomes in animals and spindle pole bodies (SPBs) in fungi, are important for the faithful distribution of chromosomes between daughter cells during mitosis as well as for other cellular functions. The cytoplasmic duplication cycle and regulation of the Schizosaccharomyces pombe SPB is analogous to centrosomes, making it an ideal model to study MTOC assembly.
Molecular model of fission yeast centrosome assembly determined by superresolution imaging. Bestul AJ1, Yu Z1, Unruh JR1, Jaspersen S J Cell Biol. 216(8):2409-2424. doi: 10.1083/jcb.201701041.
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Both the mechanism that dictates when origins become active and the biological significance of replication timing remain to be determined [...] A crucial question to be solved is how genomic regions are established that lack ORC binding. Another is whether genomic rearrangements resulting from underreplication serve biological functions. Further insights into the tissue specificity of underreplicated domains and the mechanisms of their designation will be critical to our understanding of how chromatin configuration can affect the elongation phase of DNA replication.
DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression Brian L. Hua1 and Terry L. Orr-Weaver Genetics. 207(1): 29–47. doi: 10.1534/genetics.115.186627
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DNA replication initiation requires the sequential recruitment and activation of a large number of replication protein components. Despite the conservation of the proteins governing initiation of DNA replication in eukaryotes, there are complexities in the control of metazoan DNA replication. At the most fundamental level, it remains to be determined what dictates a replication origin and where ORC will bind in metazoans [...] [...] how developmental signals modulate the activity of replication origins and forks remains to be elucidated.
DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression Brian L. Hua1 and Terry L. Orr-Weaver Genetics. 207(1): 29–47. doi: 10.1534/genetics.115.186627
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Before cell division, the genome must be completely and accurately replicated to maintain the integrity of genetic information across cell generations. [...] it is clear that the mechanisms that regulate origin activity and replication fork progression are diverse and complex, particularly in the context of development.
DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression Brian L. Hua1 and Terry L. Orr-Weaver Genetics. 207(1): 29–47. doi: 10.1534/genetics.115.186627
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Proper control of DNA replication is critical to ensure genomic integrity during cell proliferation. In addition, differential regulation of the DNA replication program during development can change gene copy number to influence cell size and gene expression.
DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression Brian L. Hua1 and Terry L. Orr-Weaver Genetics. 207(1): 29–47. doi: 10.1534/genetics.115.186627
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The centromere is a critical genomic region that enables faithful chromosome segregation during mitosis, and must be distinguishable from other genomic regions to facilitate establishment of the kinetochore. The centromere-specific histone H3-variant CENP-A forms a special nucleosome that functions as a marker for centromere specification. In addition to the CENP-A nucleosomes, there are additional H3 nucleosomes that have been identified in centromeres, both of which are predicted to exhibit specific features. It is likely that the composite organization of CENP-A and H3 nucleosomes contributes to the formation of centromere-specific chromatin, termed ‘centrochromatin’. Recent studies suggest that centrochromatin has specific histone modifications that mediate centromere specification and kinetochore assembly.
Critical histone post-translational modifications for centromere function and propagation Tatsuo Fukagawa Journal Cell Cycle ? Volume 16, 2017 - Issue 13 http://dx.doi.org/10.1080/15384101.2017.1325044
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Despite its ubiquity in interphase eukaryotic nuclei, the functional significance of the RabI configuration, in which interphase centromeres are clustered at the nuclear envelope (NE) near the centrosome and telomeres localize at the opposite end of the nucleus, has remained mysterious.
The functionally elusive RabI chromosome configuration directly regulates nuclear membrane remodeling at mitotic onset Alfonso Fernández-Álvarez & Julia Promisel Cooper Journal Cell Cycle ? Volume 16, 2017 - Issue 15, Pages 1392-1396 http://dx.doi.org/10.1080/15384101.2017.1338986
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The mammalian nuclear division cycle is coordinated with nuclear envelope breakdown (NEBD), in which the entire nuclear envelope (NE) is dissolved to allow chromosomes to access their segregation vehicle, the spindle. In other eukaryotes, complete NEBD is replaced by localized disassembly or remodeling of the NE. [...] the molecular mechanisms controlling NE disassembly are incompletely understood, coordinated cycles of modification of specific NE components drive breakdown.
Chromosomes Orchestrate Their Own Liberation: Nuclear Envelope Disassembly Alfonso Fernández-Álvarez 1, Julia Promisel Cooper Volume 27, Issue 4, Pages 255-265 Trends in Cell Biology
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The role of the conserved meiotic telomere bouquet has been enigmatic for over a century. Surprisingly, bouquet-deficient meiocytes with functional spindles harbour chromosomes that fail to achieve spindle attachment. These results reveal an unanticipated level of control of centromeres by telomeres.
The telomere bouquet regulates meiotic centromere assembly. Klutstein M, Fennell A, Fernández-Álvarez A, Cooper JP. Nat Cell Biol. 17(4):458-69. doi: 10.1038/ncb3132.
Did somebody say 'Surprisingly'? Did somebody say 'unanticipated level of control'? Complex functionally specified informational complexityDionisio
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[...] rap1-5D and rap1-5E mutants do not have any sporulation defects [15], which suggests that the bouquet is intact. This is surprising since the Rap1-Bqt4 interaction is required for telomere clustering in meiosis [8], and raises the possibility that telomeres remain associated with Bqt4 and the SPB via different mechanisms.
Telomere protein Rap1 is a charge resistant scaffolding protein in chromosomal bouquet formation Hanna Amelina, Shaan Subramaniam, Vera Moiseeva, Christine Anne Armstrong, Siân Rosanna Pearson and Kazunori Tomita BMC Biology 13:37 https://doi.org/10.1186/s12915-015-0149-x
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Telomeres are specialized nucleoprotein structures that form the natural ends of linear chromosomes. While telomeres are mostly known for their essential function in chromosome maintenance, they also play an important role in meiotic progression [...] [...] the molecular mechanisms that govern dissociation of telomeres from the SPB remain elusive.
Telomere protein Rap1 is a charge resistant scaffolding protein in chromosomal bouquet formation Hanna Amelina, Shaan Subramaniam, Vera Moiseeva, Christine Anne Armstrong, Siân Rosanna Pearson and Kazunori Tomita BMC Biology 13:37 https://doi.org/10.1186/s12915-015-0149-x
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Chromosomes reorganize in early meiotic prophase to form the so-called telomere bouquet. [...] the intrinsic negative charge of Rap1 is important for forming interactions with its binding partners. Thus, Rap1 is able to retain bouquet formation under heavily phosphorylated status.
Telomere protein Rap1 is a charge resistant scaffolding protein in chromosomal bouquet formation Hanna Amelina, Shaan Subramaniam, Vera Moiseeva, Christine Anne Armstrong, Siân Rosanna Pearson and Kazunori Tomita BMC Biology 13:37 https://doi.org/10.1186/s12915-015-0149-x
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