Back to search

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Molecular basis for genomic stability through shugoshins

Alternative title: Molekylært grunnlag for genomisk stabilitet gjennom shugosiner

Awarded: NOK 8.0 mill.

The ability of cells to divide is the very essence of life and our existence. Cells divide in our body every day hundred billion times. For each of the cell divisions, it is absolutely essential to maintain all genetic material in all newly made cells. All chromosomes need to be faithfully duplicated in mother cells and properly segregated in daughter cells without losing any genetic information. If errors happen in somatic cells and daughter cells end up having extra or lack of chromosomes, such cells are usually associated with cancers. If chromosome mis-segregation happens in reproductive cells, result is a miscarriage or fetus with congenital disorders (example Down syndrome). To prevent errors in chromosome segregation during cell division, cells have developed sophisticated control mechanisms that are still not completely understood. We are working on the key protein- shugoshin - that secures faithful chromosome segregation. Shugoshin guards the genome by making sure duplicated chromsomes stay connected until cell is ready to separate them equally in daughter cells. Our research is focusing on interactions that are positioning shugoshin within the chromosome and on interactions between shugoshin and enzymatic components controlling chromosome segregation. We are using state-of-art biophysical approaches, like cryoEM and hydrogen-deuterium exchange mass spectrometry to learn about molecular determinants of shugosin complexes. The knowledge gained from our work will contribute to a more thorough comprehension of processes leading to cancer and provide possible new avenues for fighting it.

-

Shugoshins are central players in securing unbiased partitioning of chromosomes during cell division. They serve as platform proteins that localize to centromere during cell division and can recruit several effector proteins with enzymatic and/or structural properties that assure equal chromosome segregation. We aim to identify exact modes of interaction between shugoshin and centromeric chromatin (localization module) and shugoshin and one of its effector binding partners, chromosome passenger complex (CPC). In our work we will use tandem purification from yeast cells and mass spectrometry to identify components of centromeric chromatin necessary for interaction with shougoshin. The interaction between shugoshin and CPC will be worked out with purified human proteins. In both cases, we will reconstitute complexes with purified components, determine stoichiometry, binding constants, map interactions between components and determine atomic structure of complexes. We will also investigate if two major effector proteins, protein phosphatase A (PP2A) and CPC bind the same region of shugoshin. Finally, we?ll test our findings through mutagenesis challenging complex formation in cells. The research proposed here will give comprehensive much needed molecular understanding of shugoshins - guardians of genome.

Publications from Cristin

No publications found

No publications found

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Funding Sources