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New clues about control in cell division


Mon, 09/03/2009 - 17:13

New clues about control in cell division



A new study published on Nature Cell Biology shows how cells keep segregating chromosomes under control during the cell division. One problem in this mechanism controlling the cell division could result in chromosome rearrangements and aneuploidy, both hallmarks of cancer cells.

The work has been carried out by Manuel Mendoza, the Cytokinesis and Chromosome Segregation group leader at the Centre for Genomic Regulation (CRG) and Yves Barral, principal investigator of the paper and member at the Biochemistry Department in ETH Zurich.
Cell division is completed through partition of the cytoplasm by ingression of the cleavage furrow, and the subsequent cleavage of the cell membrane into two during abscission. At the same time, the replicated chromosomes are segregated to opposite ends of the cell. Whereas cleavage furrow ingression usually proceeds concomitantly with pole ward movement of the chromosomes, abscission must take place exclusively after the last pair of sister chromatids have been pulled out of the cleavage plane.
In budding yeast and human cells, a checkpoint known as NoCut delays completion of cytoplasm division or cytokinesis when chromosome segregation is impaired. So, NoCut stops the process if chromosomes are not segregated and divided into poles apart. Inactivation of NoCut leads to premature abscission, and late-segregating chromosomes are trapped and (at least in yeast) cut by the cytokinesis machinery. Therefore NoCut is important for the maintenance of chromosome stability, because deregulated cytokinesis results in chromosome breakage, and probably chromosome rearrangements and aneuploidy – all hallmarks of cancer cells.
Barral and Mendoza had already noticed that the Aurora B kinase (Ipl1 in yeast) plays a central role in the NoCut checkpoint. Aurora B (or lpl1) is located at the spindle midzone during chromosome segregation (anaphase), and they thought that its inhibitory activity was promoted by the presence of chromosomes in the cleavage plane. An open question raised by these previous studies is, how does the NoCut pathway detect defects in chromosome segregation?
The Centre for Genomic Regulation researcher Manuel Mendoza together with the senior researcher Yves Barral from the ETH Zurich found that two basic events are necessary for cells to sense lagging chromosomes. First, Aurora B (or lpl1 in yeast cells) must be located at the spindle midzone. Second, a protein complex known as ADA, which acetylates chromosomes, must be present. These results indicate that Ipl1 acts as a “chromatin sensor” monitoring the clearance of (acetylated) chromatin away from the spindle midzone, and thus away from the cleavage plane. Thus, Aurora B (lpl1) controls if the spindle midzone is chromosome free.
These findings describe a new “quality control” in cell division process and it helps us to understand much better the cell division at the same time it shows us new functions of known elements in cell.
Reference work: Mendoza M, Norden C, Durrer K, Rauter H, Uhlmann F and Barral Y.: “A mechanism for chromosome segregation sensing by the NoCut checkpoint”. Publishing in Nature Cell Biology, March 2009, DOI: 10.1038/ncb1855.
For more information: Laia Cendrós, Communication & PPRR Dept., Centre for Genomic Regulation (CRG), Dr. Aiguader, 88 – PRBB Building, 08003 Barcelona. Tel. +34 93 316 02 37, contact.