The mechanism by which chromosomal DNA molecules are held together: entrapment within cohesin rings?
mysterious has been the trigger for what is arguably the most dramatic and one of the most highly regulated events in the life of a eukaryotic cell, the sudden disjunction of sister chromatids at the metaphase to anaphase transition. 1
Work in our lab has shown that sister chromatids are held together by a multi-subunit complex called cohesin whose Smc1 and Smc3 subunits are rod shaped proteins with ABC-like ATPases at one end of 50nm long intra-molecular anti-parallel coiled coils. At the other ends are pseudo-symmetrical hinge domains that interact to create V shaped Smc1/Smc3 heterodimers. N- and C-terminal domains within cohesin’s third subunit, known as α kleisin, bind to Smc3 and Smc1 ATPase heads respectively, thereby creating a huge tripartite ring whose integrity is essential for holding sister DNAs together. A thiol protease called separase opens the cohesin ring by cleaving its α kleisin subunit, which causes cohesin’s dissociation from chromosomes and triggers sister chromatid disjunction.
Regulation of chromosome condensation and segregation. 2
Regulated and controlled chromosome condensation and segregation is essential for the transmission of genetic information from one generation to the next. A myriad of techniques has been utilized over the last few decades to identify proteins required for the organized compaction of the massive length of a cell's DNA. A full understanding of the components and processes involved relies on further work, exploiting biochemical, genetic, cytological, and proteomics approaches to complete the picture of how a cell packages and partitions its genome during the cell cycle.
Condensins: universal organizers of chromosomes with diverse functions 3
Condensins are multisubunit protein complexes that play a fundamental role in the structural and functional organization of chromosomes in the three domains of life. Most eukaryotic species have two different types of condensin complexes, known as condensins I and II, that fulfill nonoverlapping functions and are subjected to differential regulation during mitosis and meiosis.
The multisubunit condensin complex is essential for the structural organization of eukaryotic chromosomes during their segregation by the mitotic spindle 4
Recruitment of the conserved centromeric protein shugoshin is essential for biorientation, but its exact role has been enigmatic. 5
A mystery surrounding tubulin, the protein that plays a crucial role in the passing of genetic material from a parent cell to daughter cells, has been at least partially solved. 6 Nogales and her colleagues also identified a region in Dam1 essential for the regulation of the complex, by spindle-checkpoint kinase enzymes. "These kinases are signaling proteins that, based on tension in the spindles, tell the ring when the time is right for it to let go of the microtubules," Nogales says. "We have found that without this region, the ability of the Dam1 to form a ring is reduced."
All eukaryotic cells must segregate their chromosomes equally between two daughter cells at each division. This process needs to be robust, as errors in the form of loss or gain of genetic material have catastrophic effects on viability. Chromosomes are captured, aligned, and segregated to daughter cells via interaction with spindle microtubules mediated by the kinetochore. 7
Topoisomerase II enzymes 8 are essential in the separation of entangled daughter strands during replication. This function is believed to be performed by topoisomerase II in eukaryotes and by topoisomerase IV in prokaryotes. Failure to separate these strands leads to cell death.
Controlled transport of macromolecules between the cytoplasm and nucleus is essential for homeostatic regulation of cellular functions. For instance, gene expression entails coordinated nuclear import of transcriptional regulators to activate transcription and nuclear export of the resulting messenger RNAs for cytoplasmic translation. Thus, Ddx19 participates in mRNA export, translation and nuclear import of a key transcriptional regulator. 9
Cell membranes are crucial to the life of the cell. 10
Nucleo-cytoplasmic transport of RNAs and proteins is essential for eukaryotic gene expression. 11
The field of mitochondrial ion channels has recently seen substantial progress, including the molecular identification of some of the channels. An integrative approach using genetics, electrophysiology, pharmacology, and cell biology to clarify the roles of these channels has thus become possible. It is by now clear that many of these channels are important for energy supply by the mitochondria and have a major impact on the fate of the entire cell as well. 12
Mammalian mtDNA only encodes 13 proteins, but these are nevertheless essential for cell viability as they are crucial components of the oxidative phosphorylation system, located in the inner mitochondrial membrane 13
In eukaryotes, lipid metabolism requires the function of peroxisomes. These multitasking organelles are also part of species-specific pathways such as the glyoxylate cycle in yeast and plants or the synthesis of ether lipid in mammals.Peroxisomal function is essential for life. 14
Fatty acids are aliphatic acids fundamental to energy production and storage, cellular structure and as intermediates in the biosynthesis of hormones and other biologically important molecules. 15
Coenzyme A (CoA) is an essential cofactor in numerous metabolic and energy-yielding reactions and is involved in the regulation of key metabolic enzymes 16
γ-tubulin is essential for normal microtubule organization in every organism in which it has been studied, and it is nearly ubiquitous throughout the eukaryotes 17
Su48 represents a previously unrecognized centrosome protein that is essential for cell division18
The ab tubulin heterodimer is the structural subunit of microtubules, which are cytoskeletal elements that are essential for intracellular transport and cell division in all eukaryotes. 19
Presently, the best studied are the mitotic Kinesin-13 proteins. Studies in both D. melanogaster and human cells suggest a division of labor between Kinesin-13 family members, such that different proteins contribute microtubule depolymerizing activity to the centrosome and centromere during mitosis. These activities have been shown to be essential for spindle morphogenesis and chromosome segregation. 20
During cell division, mitotic spindles are assembled by microtubule-based motor proteins1, 2. The bipolar organization of spindles is essential for proper segregation of chromosomes, and requires plus-end-directed homotetrameric motor proteins of the widely conserved kinesin-5 (BimC) family 21
The various functions of the Endoplasmic Reticulum are essential to every cell, their relative importance varies greatly between individual cell types.
Cotranslational translocation of proteins across or into membranes is a vital process in all kingdoms of life. 22
Telomeres, the specialized nucleoprotein structures that cap the ends of linear chromosomes, are essential for genome integrity and hence cell viability because they protect chromosome ends from fusions and degradation. 23
Initiation of cellular DNA replication is tightly controlled to sustain genomic integrity. In eukaryotes, the heterohexameric origin recognition complex (ORC) is essential for coordinating replication onset.
DNA helicases are essential during DNA replication because they separate double-stranded DNA into single strands allowing each strand to be copied.
8 ) https://en.wikipedia.org/wiki/Type_II_topoisomerase
24) http://www.nature.com/nature/journal/v519/n7543/full/nature14239.html Nature 519, 321–326(19 March 2015) doi:10.1038/nature14239