Loss of control kills germ cells

Protein prevents premature chromosomal decay

Chromosomes of a germ cell Vienna Biocenter
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In the development of egg and sperm some things can go wrong. There are a number of diseases and disorders that arise as a result of premature decay of the chromosomes during cell division. Why this is so and what prevents it, Vienna scientists have now found out.

During cell division of body cells called mitosis, freshly doubled chromosomes are split among the daughter cells. Cell division is different in the development of germ cells - oocytes and spermatozoa. In this cell division, called meiosis, the two-fold set of chromosomes - maternal and paternal - found in every cell in the body must be reduced to a single one.

Professor Franz Klein and his colleague, PhD student Alexandra Penkner, from Vienna Biocenter have now published in the journal CELL results on an important regulation of this process. These show that cell death leading to premature cleavage of newly duplicated chromosomes by a protein called Mnd2 is prevented.

Sisters hold together

As for the background of the work done on the model organism Saccharomyces cerevisiae, brewer's yeast, Klein explains: "The newly doubled chromosomes, also called sister chromatids, are held together by a protein ring called cohesin until their separation. In this case, the chromatids are arranged so that later a correct division takes place on the progeny cells. The task of the protein Mnd2, which we have now discovered, is to stabilize this order until the correct time is reached during cell division. "

The opening of the cohesin rings necessary for cell division is controlled by the so-called Anaphase Promoting Complex (APC / C). Klein said: "Even while we were working on Mnd2, colleagues in the US and Germany found that ad

Mnd2 is one of 13 fixed parts of the APC / C, but no one knew what a significant role Mnd2 played. This manifests itself exclusively during meiosis, when the germ cells are created. "

Penkner initially showed experimentally that cells lacking Mnd2 show damage to the meiotic chromosome structure, DNA breaks, and premature separation of sister chromatids. Such anomalies could be caused by unregulated APC / C activity. This assumption was tested by Penkner in elegant experiments in which she used yeast cells

- in addition to Mnd2 - also inactivated the APC / C. In fact, the chromosome damage could be prevented.

A protein as a brake

Further experiments provided the explanation for the phenomenon that the described damage occurs exclusively during meiosis. It has been shown that Mnd2 inhibits an additional subunit (Ama1) of the APC / C, which occurs only during meiosis and serves to activate the APC / C. If Mnd2 is missing, the APC / C will be activated too early by the amy1 during meiosis and the protein rings will be opened unrestrained. Thus, the connection between the sister chromatids is lost prematurely, which has chromosomal damage and ultimately cell death as a consequence.

Especially in meiosis, such chromosome damage is of particular importance. An example in humans is the Down syndrome, which arises because the "fair" division of two chromosomes does not work. This results in germ cells with two chromosomes 21, which after fertilization grow into body cells with three chromosomes 21.

Klein's work follows an earlier joint study with a team led by Professor Kim Nasmyth of the Research Institute of Molecular Pathology (IMP) at the Campus Vienna Biocenter. In this work, the role of over 300 proteins during meiosis was analyzed. It was also discovered that Mnd2 has a crucial function - which could now be explained in the present work with the support of the FWF.

(Vienna Biocenter, 30.03.2005 - NPO)