Chromosome segregation
Home 
departments Molecular Biology Chromosome segregation
Fernando Monje CasasResearch areas:
- Regulation of chromosome segregation.
- Regulation of the Mitotic Exit Network (MEN).
- Cell cycle checkpoints.
Group info:
Our group focuses on the mechanisms that regulate the segregation of the chromosomes, both during mitosis and during meiosis. An incorrect segregation of the chromosomes can lead to aneuploidy, a condition that is defined by an alteration of the normal number of chromosomes in the cell and that is a hallmark of cancer and a number of different diseases.
We are specifically interested in the regulation of the mitotic exit network (MEN), a signaling cascade that determines the exit from mitosis, which is the final cell cycle transition that leads to the production of two genetically-identical daughter cells. Bfa1 and Bub2 constitute a two-component GTPase activating protein (GAP) that negatively regulates Tem1, a GTPase that acts at the top of the cascade. Bfa1 and Bub2 maintain Tem1 in an inactive GDP-bound form during most of the cell cycle. Apart from being key components of the MEN, Bfa1 and Bub2 are essential members of three different surveillance mechanisms that regulate the fidelity in the transmission of the genomic material:
- The DNA damage checkpoint: a surveillance mechanism that arrests cell cycle to provide time for the cells to repair DNA damage resulting from radiation, reactive oxygen species and replication errors.
- The spindle assembly checkpoint: a regulatory mechanism that ensures that every chromosome has been attached to the mitotic spindle, and delays the onset of anaphase until all the kinetochores are linked to the spindle in a bipolar fashion.
- The spindle position checkpoint (SPOC): a surveillance mechanism that avoid that cells with a misaligned spindle exit from mitosis, which would lead to the generation of aneuploid cells.
We are also interested in determining the mechanisms by which Aurora B kinase (Ipl1 in budding yeast) regulates the proper attachment of the chromosomes to the spindle in a bipolar fashion. Ipl1 corrects syntelic attachments of the chromosomes to the spindle (when both kinetochores of the sister chromatids attach to the same spindle pole), and activates the spindle assembly checkpoint to block cell cycle progression until the appropriate bipolar attachments are established. We are trying to decipher the actual mechanisms that underlie this process and to better understand the relationship between the spindle assembly checkpoint and Aurora B kinase.
The long-term aim of our laboratory is to check whether the mechanisms that we demonstrate to regulate chromosome segregation in budding yeast operate in a similar way in cells from higher organisms. The proteins that constitute the SAC and the Aurora kinase family show a high degree of conservation from yeast to higher eukaryotes. The SAC is essential in mammals, and homozygotic mutations in genes that code for components of the SAC lead to embryonic lethality due to chromosome segregation problems. The SAC is also important during the somatic cell cycle in mammals, and it has been demonstrated that problems in the SAC are related to carcinogenic processes. On the other hand, and even though the SPOC is specific for budding yeast due to their particular way of cell division, several studies suggest that mechanisms that regulate mitotic spindle positioning might exist in higher organisms in cells that show some type of polarity. For example, in epithelial cells spindle orientation is important to maintain the integrity of the epithelial barrier. Thus, it would be interesting to determine whether these processes depend on mechanisms that are similar to those found in yeast.
Funding:
Research projects funded by:
Spanish Ministry of Science and Innovation (BFU2011-23436).
7th Framework Programme. European Comission, CORDIS (FP7-239416).
Junta de Andalucía (CVI-5806).
FEDER funds.
Postdocs and PhD students supported by:
Spanish Ministry of Science and Innovation.
7th Framework Programme. European Comission, CORDIS.
FEDER funds.
Spanish National Research Council (CSIC).
Selected Publications:
Tem1 localization to the spindle pole bodies is essential for mitotic exit and impairs spindle checkpoint function
Valerio-Santiago M, Monje-Casas F.
The Journal of Cell Biology (2011). 192(4):599-614.
Cell polarity determinants establish asymmetry in MEN signaling
Monje-Casas F, Amon A.
Developmental Cell (2009). 16(1):132-145.
Regulation of Spo12 phosphorylation and its essential role in the FEAR network
Tomson BN, Rahal R, Reiser V, Monje-Casas F, Mekhail K, Moazed D, Amon A.
Current Biology (2009). 19(6):449–460.
Kinetochore orientation during meiosis is controlled by Aurora B and the monopolin complex
Monje-Casas F, Prabhu VR, Lee BH, Boselli M, Amon A.
Cell (2007). 128(3):477-490.
The protein kinase Kin4 inhibits exit from mitosis in response to spindle position defects
D'Aquino KE, Monje-Casas F, Paulson J, Reiser V, Charles GM, Lai L, Shokat KM, Amon A.
Molecular Cell (2005). 19(2):223-234.
954 468 004 | 
