Dyskerin, tRNA genes, and condensin tether pericentric chromatin to the spindle axis in mitosis

Snider, Chloe E.; Stephens, Andrew D.; Kirkland, Jacob G.; Hamdani, Omar; Kamakaka, Rohinton T.; Bloom, Kerry

doi:10.1083/jcb.201405028

Cited by 30 publications

(36 citation statements)

References 41 publications

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“…This may be perceived as active condensation, but it is a natural consequence of random stepping on a thermally fluctuating chain. Likewise, condensin can appear to concentrate in particular locations, such as within the pericentromere and the nucleolus (Bachellier-Bassi et al 2008;Stephens et al 2013;Snider et al 2014). This has been interpreted as oligomerization between condensin holoenzymes or other cross-linking proteins.…”

Section: Resultsmentioning

confidence: 99%

RotoStep: A Chromosome Dynamics Simulator Reveals Mechanisms of Loop Extrusion

Lawrimore

Friedman

Doshi

et al. 2017

Cold Spring Harb Symp Quant Biol

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ChromoShake is a three-dimensional simulator designed to explore the range of configurational states a chromosome can adopt based on thermodynamic fluctuations of the polymer chain. Here, we refine ChromoShake to generate dynamic simulations of a DNA-based motor protein such as condensin walking along the chromatin substrate. We model walking as a rotation of DNAbinding heat-repeat proteins around one another. The simulation is applied to several configurations of DNA to reveal the consequences of mechanical stepping on taut chromatin under tension versus loop extrusion on single-tethered, floppy chromatin substrates. These simulations provide testable hypotheses for condensin and other DNA-based motors functioning along interphase chromosomes. Our model reveals a novel mechanism for condensin enrichment in the pericentromeric region of mitotic chromosomes. Increased condensin dwell time at centromeres results in a high density of pericentric loops that in turn provide substrate for additional condensin.There has been a revolution in understanding the higher-order structure and organization of chromosome in the past decade. Several major approaches (3C, ChromEMT, and super-resolution microscopy) are indicative of a disordered array of loopy fibers that emanate from an axial core (Dostie and Bickmore 2012;Dekker et al. 2013;Ou et al. 2017). The hierarchical models of structural intermediates building from 11 to 30 nm and larger fibers are not borne out in these recent 3D and live-cell studies (Ou et al. 2017). DNA looping was first observed in squash preparations of salamander eggs under the light microscope by the embryologist Oskar Hertwig in the early 1900s (Hertwig 1906). Paulson and Laemmli (1977) observed DNA loops when examining chromosome spreads in isolated mammalian cells. In metaphase, the loops emanate from a protein-rich chromosome scaffold. The chromosome scaffold is enriched in topology-adjusting proteins, such as topoisomerase II and the SMC (structural maintenance of chromosomes) proteins, known as condensin (Earnshaw et al. 1985;Hirano 2006).Loops are a natural consequence of the entropic fluctuations and excluded volume interactions of tethered polymer chains in a confined space, such as the nucleus (Vasquez et al. 2016). If we consider the genome as a ball of yarn, the formation of loops can be appreciated as chains that randomly collide and wiggle around one another. Energy-requiring processes are also involved in loop formation. The earliest suggestion of loop extrusion came from the trombone model of DNA replication (Sinha et al. 1980;Alberts et al. 1983) and direct visualization of DNA looping at the replication fork (Park et al. 1998). More recently, SMC proteins (e.g., cohesin and condensin), which bind and hydrolyze ATP, have been cited as having loop extrusion potential (Alipour and Marko 2012). Condensin has garnered attention based on recent studies showing it to be a DNA translocase (Terekawa et al. 2017).Condensin is composed of five subunits, two coiledcoils SMC2 and 4, a kleisin ...

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Section: Resultsmentioning

confidence: 99%

RotoStep: A Chromosome Dynamics Simulator Reveals Mechanisms of Loop Extrusion

Lawrimore

Friedman

Doshi

et al. 2017

Cold Spring Harb Symp Quant Biol

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“…14 This hypothesis predicts that the pericentromere from one chromosome will be detached upon removal of all tDNA genes throughout the chromosome. 14 Toward this end, tDNA genes were removed from chromosome III, the essential tDNA genes relocated to other chromosomes to ensure survival of the mutant strain.…”

Section: Resultsmentioning

confidence: 99%

“…Condensin functions to cross-link pericentromeres of neighboring chromosomes to the central spindle axis. 14,36 However, depletion of nucleosomes does not disrupt inter-pericentromere cross-linking. Thus, disruption of the cross-linked pericentromere network is more likely to result in displacement of LacO from the spindle axis as seen only in condensin mutants (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Depletion of dyskerin or monopolin results in a 40-60% depletion of pericentric condensin and a loss of alignment along the spindle axis. 14 The proximity of the distal pericentromere LacO to the spindle axis did not change upon their depletion (177-187 nm, n D 50 and 86, p > 0.05, Fig. 2C).…”

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confidence: 99%

“…The mechanism of clustering may reside in the binding to tRNA genes. 14,42 It has been reported that sumoylation can modulate the clustering or cooperative binding of proteins. [22][23][24][25] Our evidence suggest a similar mechanism for the control of condensin clustering as excess sumoylation (smt4D) results in pericentric condensin declustering (Fig.…”

Section: 38mentioning

confidence: 99%

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The SUMO deconjugating peptidase Smt4 contributes to the mechanism required for transition from sister chromatid arm cohesion to sister chromatid pericentromere separation

2015

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T he pericentromere chromatin protrudes orthogonally from the sistersister chromosome arm axis. Pericentric protrusions are organized in a series of loops with the centromere at the apex, maximizing its ability to interact with stochastically growing and shortening kinetochore microtubules. Each pericentromere loop is »50 kb in size and is organized further into secondary loops that are displaced from the primary spindle axis. Cohesin and condensin are integral to mechanisms of loop formation and generating resistance to outward forces from kinesin motors and anti-parallel spindle microtubules. A major unanswered question is how the boundary between chromosome arms and the pericentromere is established and maintained. We used sister chromatid separation and dynamics of LacO arrays distal to the pericentromere to address this issue. Perturbation of chromatin spring components results in 2 distinct phenotypes. In cohesin and condensin mutants sister pericentric LacO arrays separate a defined distance independent of spindle length. In the absence of Smt4, a peptidase that removes SUMO modifications from proteins, pericentric LacO arrays separate in proportion to spindle length increase. Deletion of Smt4, unlike depletion of cohesin and condensin, causes stretching of both proximal and distal pericentromere LacO arrays. The data suggest that the sumoylation state of chromatin topology adjusters, including cohesin, condensin, and topoisomerase II in the pericentromere, contribute to chromatin spring properties as well as the sister cohesion boundary.

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Tension sensors reveal how the kinetochore shares its load

Salmon

Bloom

2017

BioEssays

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At metaphase in mitotic cells, pulling forces at the kinetochore-microtubule interface create tension by stretching the centromeric chromatin between oppositely oriented sister kinetochores. This tension is important for stabilizing the end-on kinetochore microtubule attachment required for proper bi-orientation of sister chromosomes as well as for satisfaction of the Spindle Assembly Checkpoint and entry into anaphase. How force is coupled by proteins to kinetochore microtubules and resisted by centromere stretch is becoming better understood as many of the proteins involved have been identified. Recent application of genetically encoded fluorescent tension sensors within the mechanical linkage between the centromere and kinetochore microtubules are beginning to reveal – from live cell assays – protein specific contributions that are functionally important.

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Dyskerin, tRNA genes, and condensin tether pericentric chromatin to the spindle axis in mitosis

Abstract: Pericentric enrichment of condensin on budding yeast chromosomes, which contributes to chromatin compaction and mitotic spindle structure and integrity, is mediated by condensin interaction with tRNA genes and the tRNA-interacting protein dyskerin.

Cited by 30 publications

References 41 publications

RotoStep: A Chromosome Dynamics Simulator Reveals Mechanisms of Loop Extrusion

RotoStep: A Chromosome Dynamics Simulator Reveals Mechanisms of Loop Extrusion

The SUMO deconjugating peptidase Smt4 contributes to the mechanism required for transition from sister chromatid arm cohesion to sister chromatid pericentromere separation

Tension sensors reveal how the kinetochore shares its load

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