Protein Mnd2 protects chromosome bonds

The protein Mnd2 inhibits premature separation of chromosomes during the formation of gametes. The now published discovery of this regulatory function may help to understand the origin of some common congenital chromosome defects. The project of a team of the University of Vienna funded by the Austrian Science Fund (FWF) contributes to the Campus Vienna Biocenter maintaining a top-level position in the field of cell division research.

During the division of somatic cells (mitosis) newly duplicated chromosomes (sister chromatids) separate and segregate to opposite daughter cells. The cell division, which leads to the formation of gametes (egg and sperm cells), serves a different purpose. In this cell division called meiosis, the two complete sets of chromosomes (maternal and paternal ones) in each body cell are reduced to a single one.

Prof. Franz Klein and his colleague, Ph.D. student Alexandra Penkner from the Department of Chromosome Biology of the Max Perutz Laboratories at the Campus Vienna Biocenter, have now published results on an important regulation of this process in the journal CELL. These findings show that the premature segregation of sister chromatids with lethal consequences are inhibited by a protein named Mnd2.

The research carried out on the model organism Saccharomyces cerevisiae (yeast) is explained by Prof. Klein, "Until they are separated, the sister chromatids are linked by a protein ring called cohesin. This linkage ensures their correct segregation to the daughter cells later on. We have now discovered an important role of the protein Mnd2 in stabilising this arrangement up to the right moment in the cell division."

The command for opening the cohesin rings, which initiates the division, comes via the anaphase promoting complex (APC/C). Klein explains, "While we worked on Mnd2, colleagues in the USA and Germany isolated Mnd2 as one of 13 subunits of the APC/C. However, the important role of Mnd2 was not revealed. Because only during meiosis, when the gametes are created, does it become essential."

In initial experiments, Ms. Penkner observed defects in meiotic chromosome structure, DNA breaks and premature separation of sister chromatides in cells lacking Mnd2. Such abnormalities may be caused by an irregular activity of the APC/C. To verify this idea, Ms. Penkner conducted clever experiments in which she inactivated the APC/C in yeast cells in addition to Mnd2. Indeed without a functional APC/C, Mnd2 was not anymore required to prevent chromosomal defects.

Additional experiments explained why the described damages occurred exclusively during meiosis. An activator of the APC/C (Ama1), which only appears during meiosis, requires Mnd2. It is Ama1, which activates the APC/C too early in the absence of Mnd2 and thus opens the cohesin rings prematurely, that leads to chromosome damage and finally to the death of the cell.

Chromosome damage in meiosis can have lasting consequences. Well-known examples are Down Syndrome patients, for whom the proper division of two chromosomes did not occur during the meiosis of one parent. The fusion of two germ cells, one of which carried two copies of chromosomes 21, gave rise to body cells carrying three chromosomes 21.

The work of Prof. Klein follows an earlier joint study with a team led by Prof. Kim Nasmyth from the Research Institute of Molecular Pathology (IMP) at the Campus Vienna Biocenter. In that research, the role of over 300 proteins during meiosis was analysed. Consequently, Mnd2 was recognised as important meiotic function, which could now be worked out with support from the FWF.