Chromosomal cleavage

Olivacine (52) and ellipticine (53) are antileukemic agents in mice, and derivatives of ellipticine are used clinically in Europe (Fig. 34.14) (CordeU, 1978 Gribble, 1990). The principal mechanism of action is related to the planar structures of this group of alkaloids. Ellipticine and its derivatives appear to inhibit topoisomerase II they also are mutagenic and clastogenic at the tk locus of mouse lymphoma cells. The major mechanism of action appears to be chromosomal cleavage (Bonis and Schaeffer, 1992 Gribble, 1990). These alkaloids inhibit DNA synthesis by intercalation into DNA. 9-Methoxyellipticine and ellipticine inhibit mitochondrial respiration and cytochrome c oxidase (Wink, 1993). 

It is possible to observe effects of organotin(lV) compounds exposure such as inhibition of cleavage of fertilized eggs, interference with the formation of the mitotic spindle, damages affecting chromosome structure, and electron-dense precipitate formation in organelles. 

The non-cleavage pathway would remove most cohesin during prophase/ pro-metaphase by an as yet obscure mechanism. This pathway could involve phosphorylation of a cohesin subunit by mitotic protein kinases, because vertebrate cohesins rebind to chromatin in telophase when mitotic kinases are inactivated and chromosomes decondense (Losada et al 1998). The dissociation of cohesin from chromatin during prophase coincides with, but does not depend on, the association of condensin with chromosomes. This first phase of cohesin removal may be crucial (possibly along with the arrival of... 

Amon 1999). In most, but not all eukaryotic cells, unaligned or lagging chromosomes transmit a signal via the protein Mad2, which inhibits the APC and its activator protein Cdc20 and thereby prevents the proteolysis of both 13-type cyclins and securins. It is the block to securin destruction that prevents Sccl cleavage and thereby sister chromatid separation (Fig. 5) (Alexandru et al 1999). 

The pall of fog that has shrouded the sister separation process for over a century is starting to lift and this long mysterious process has started to reveal its secrets. There is now convincing evidence that the sudden movement of chromosomes to the poles at the onset of anaphase is triggered by cleavage of specific sister chromatid cohesion proteins. Future research must address the structural basis of cohesion and how it is established only at replication forks. It must also address the generality of mechanisms that dismantle cohesion at the metaphase to anaphase transition and how mistakes in this process contribute to human disease. 

Uhlmann F, Lottspeich F, Nasmyth K 1999 Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Sccl. Nature 400 37-42 vanHeemst D, James F, Poggeler S, Berteaux-Lecellier V, ZicklerD 1999 Spo76p is a conserved chromosome morphogenesis protein that links the mitotic and meiotic programs. Cell 98 261-271... 

Nasmyth In the yeast, most of the cleavage takes place in a Polo mutant, and the centromeres go to the poles quite normally. But the chromosomes don t fully disengage. We suspect about 10% of the Sccl may not be coming off. If you make a Pdsl /Polo double mutant (which is difficult because they are almost synthetic lethal), then it looks like there isn t much anaphase at all. But these are recent, preliminary results. 

It is clear that both intact cell MALDI-TOF and PFGE have their limitations. PFGE analyses probes the chromosomal DNA of microorganisms for variations in the locations of specific restriction enzyme cleavage sites, while MALDI-TOF mass spectrometry of intact cells primarily examines abundant proteins such as ribosomal proteins35 and those associated with or near bacterial cell walls.58 In order for MALDI-TOF to detect a variation, a mutation must lead to noticeable changes in the expression of cell wall—associated... 

Cleavage of cystathionine is accomplished by cystathi-onase, another pyridoxine-dependent enzyme that is coded on human chromosome 16 (Fig. 40-4 reaction 6). The enzyme functions almost entirely to produce cysteine, there being virtually no reversal of the reaction. 

Razin SV, Petrov P, Hancock R (1991) Precise localization of the alpha-globin gene cluster within one of the 20- to 300-kilobase DNA fragments released by cleavage of chicken chromosomal DNA at topoisomerase 11 sites in vivo evidence that the fragments are DNA loops or domains. Proc Natl Acad Sci USA 88(19) 8515-8519... 

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