How two become one: HJURP dimerization drives CENP-A assembly

CENP‐A containing nucleosomes epigenetically specify centromere position on chromosomes. Deposition of CENP‐A into chromatin is mediated by HJURP, a specific CENP‐A chaperone. Paradoxically, HJURP binding sterically prevents dimerization of CENP‐A, which is critical to form functional centromeric nucleosomes. A recent publication in The EMBO Journal (Zasadzińska et al, 2013) demonstrates that HJURP itself dimerizes through a C‐terminal repeat region, which is essential for centromeric assembly of nascent CENP‐A.FCT fellowship: (SFRH/BD/74284/2010); FCT grants: (BIA-BCM/100557/2008, BIAPRO/100537/2008); EMBO Installation Grant

Of Cell Shapes and Motion: The Physical Basis of Animal Cell Migration.

Motile cells have developed a variety of migration modes relying on diverse traction-force-generation mechanisms. Before the behavior of intracellular components could be easily imaged, cell movements were mostly classified by different types of cellular shape dynamics. Indeed, even though some types of cells move without any significant change in shape, most cell propulsion mechanisms rely on global or local deformations of the cell surface. In this review, focusing mostly on metazoan cells, we discuss how different types of local and global shape changes underlie distinct migration modes. We then discuss mechanical differences between force-generation mechanisms and finish by speculating on how they may have evolved

Cdk Activity Couples Epigenetic Centromere Inheritance to Cell Cycle Progression

Centromeres form the site of chromosome attachment to microtubules during mitosis. Identity of these loci is maintained epigenetically by nucleosomes containing the histone H3 variant CENP-A. Propagation of CENP-A chromatin is uncoupled from DNA replication initiating only during mitotic exit. We now demonstrate that inhibition of Cdk1 and Cdk2 activities is sufficient to trigger CENP-A assembly throughout the cell cycle in a manner dependent on the canonical CENP-A assembly machinery. We further show that the key CENP-A assembly factor Mis18BP1(HsKNL2) is phosphorylated in a cell cycle-dependent manner that controls its centromere localization during mitotic exit. These results strongly support a model in which the CENP-A assembly machinery is poised for activation throughout the cell cycle but kept in an inactive noncentromeric state by Cdk activity during S, G2, and M phases. Alleviation of this inhibition in G1 phase ensures tight coupling between DNA replication, cell division, and subsequent centromere maturation.FCT doctoral fellowship: (SFRH/BD/33219/2007); FCT grant: (BIA-BCM/100557/2008); Fundação Calouste Gulbenkian; European Commission FP7 programme; EMBO installation grant

A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly

The deposited article is a post-print version and has peer review. The deposited article version contains attached the supplementary materials within the pdf. This publication hasn't any creative commons license associated.Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation. Simultaneous expression of mutant proteins lacking these residues results in complete uncoupling from the cell cycle. Consequently, CENP-A assembly is fully recapitulated under high Cdk activities, indistinguishable from G1 assembly. We find that Cdk-mediated inhibition is exerted by sequestering active factors away from the centromere. Finally, we show that displacement of M18BP1 from the centromere is critical for the assembly mechanism of CENP-A.Fundação para a Ciência e a Tecnologia grants: (SFRH/BD/51878/2012, SFRH/BD/74284/2010, BIA-BCM/100557/2008); NIH/National Institute of General Medical Sciences grants: (R01-GM082989; T32-GM008275); NIH/NCI grant: (F30-CA186430); NIH grants (GM 037537, GM 110174); EMBO installation grant: (1818); ERC-consolidator grant: (ERC-2013-CoG-615638).info:eu-repo/semantics/publishedVersio

Microtubule nucleation from the fibrous corona by LIC1-pericentrin promotes chromosome congression

Error-free chromosome segregation in mitosis and meiosis relies on the assembly of a microtubule-based spindle that interacts with kinetochores to guide chromosomes to the cell equator before segregation in anaphase. Microtubules sprout from nucleation sites such as centrosomes, but kinetochores can also promote microtubule formation. It is unclear, however, how kinetochore-derived microtubules are generated and what their role is in chromosome segregation. Here, we show that the transient outer-kinetochore meshwork known as the fibrous corona serves as an autonomous microtubule nucleation platform. The fibrous corona is essential for the nucleation of kinetochore-derived microtubules, and when dissociated from the core kinetochore, it retains microtubule nucleation capacity. Nucleation relies on a fibrous-corona-bound pool of the LIC1 subunit of the dynein motor complex, which interacts with the γ-tubulin-tethering protein pericentrin (PCNT). PCNT is essential for microtubule nucleation from fibrous coronas, and in centrosome-depleted cells, where nearly all mitotic nucleation occurs at fibrous coronas, chromosome congression is fully dependent on PCNT. We further show that chromosomes in bovine oocytes, which naturally lack centrosomes, have highly expanded fibrous coronas that drive chromosome-derived microtubule nucleation. Preventing fibrous corona expansion in these cells impairs chromosome congression and causes spindle assembly defects. Our results show that fibrous coronas are autonomous microtubule-organizing centers that are important for spindle assembly, which may be especially relevant in acentrosomal cells such as oocytes

Cdk activity couples epigenetic centromere inheritance to cell cycle progression

Centromeres form the site of chromosome attachment to microtubules during mitosis. Identity of these loci is maintained epigenetically by nucleosomes containing the histone H3 variant CENP-A. Propagation of CENP-A chromatin is uncoupled from DNA replication initiating only during mitotic exit. We now demonstrate that inhibition of Cdk1 and Cdk2 activities is sufficient to trigger CENP-A assembly throughout the cell cycle in a manner dependent on the canonical CENP-A assembly machinery. We further show that the key CENP-A assembly factor Mis18BP1(HsKNL2) is phosphorylated in a cell cycle-dependent manner that controls its centromere localization during mitotic exit. These results strongly support a model in which the CENP-A assembly machinery is poised for activation throughout the cell cycle but kept in an inactive noncentromeric state by Cdk activity during S, G2, and M phases. Alleviation of this inhibition in G1 phase ensures tight coupling between DNA replication, cell division, and subsequent centromere maturatio

The quantitative architecture of centromeric chromatin.

The centromere, responsible for chromosome segregation during mitosis, is epigenetically defined by CENP-A containing chromatin. The amount of centromeric CENP-A has direct implications for both the architecture and epigenetic inheritance of centromeres. Using complementary strategies, we determined that typical human centromeres contain ∼400 molecules of CENP-A, which is controlled by a mass-action mechanism. This number, despite representing only ∼4% of all centromeric nucleosomes, forms a ∼50-fold enrichment to the overall genome. In addition, although pre-assembled CENP-A is randomly segregated during cell division, this amount of CENP-A is sufficient to prevent stochastic loss of centromere function and identity. Finally, we produced a statistical map of CENP-A occupancy at a human neocentromere and identified nucleosome positions that feature CENP-A in a majority of cells. In summary, we present a quantitative view of the centromere that provides a mechanistic framework for both robust epigenetic inheritance of centromeres and the paucity of neocentromere formation.DOI: http://dx.doi.org/10.7554/eLife.02137.001

Deeprank2

What's Changed Fix fix: check only 1 pssm for variant queries by @DaniBodor in https://github.com/DeepRank/deeprank2/pull/430 fix: pdb files with underscore in the filename gives unexpected query ids by @joyceljy in https://github.com/DeepRank/deeprank2/pull/447 fix: dataset_train inheritance warnings by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/461 fix: cast hse feature to float64 by @DanLep97 in https://github.com/DeepRank/deeprank2/pull/465 fix: readthedocs after deeprank2 renaming by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/472 fix: force scipy version for fixing deeprank2 installation by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/478 fix: warning messages for invalid data in test_dataset.py by @joyceljy in https://github.com/DeepRank/deeprank2/pull/442 fix: make scipy 1.11.2 work by @cbaakman in https://github.com/DeepRank/deeprank2/pull/482 Refactor refactor: inherit information from training set for valid/test sets by @joyceljy in https://github.com/DeepRank/deeprank2/pull/446 refactor: rename deeprankcore to deeprank2 by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/469 Build build: improve installation making use of pyproject.toml file only and setuptools by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/491 CI CI: decrease sensitivity of test_graph_augmented_write_as_grid_to_hdf5 by @DaniBodor in https://github.com/DeepRank/deeprank2/pull/445 CI: fewer triggers by @DaniBodor in https://github.com/DeepRank/deeprank2/pull/457 Docs docs: update README.md by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/443 docs: create tutorial README by @DaniBodor in https://github.com/DeepRank/deeprank2/pull/455 docs: improve installation instructions by @DaniBodor in https://github.com/DeepRank/deeprank2/pull/452 docs: add tutorials for PPIs by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/434 docs: add tutorials for variants by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/459 docs: minor improvements to install instructions by @DaniBodor in https://github.com/DeepRank/deeprank2/pull/484 docs: type hinting and docstrings in molstruct by @DaniBodor in https://github.com/DeepRank/deeprank2/pull/497 docs: joss paper by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/423 docs: clarify ppi scoring metrics and add doc strings and tests by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/498 docs: add performances table for deeprank2 by @gcroci2 in https://github.com/DeepRank/deeprank2/pull/493 Style style: auto-scrape trailing whitespace upon save in VS code by @DaniBodor in https://github.com/DeepRank/deeprank2/pull/483 Full Changelog: https://github.com/DeepRank/deeprank2/compare/v2.0.0...v2.1.