Principles of Chromosome Segregation and Consequences of Defective Segregation

Research interests

We are interested in understanding the biochemical principles that govern the segregation of human chromosomes during cell division. Defects in chromosome segregation can lead to irregular chromosome numbers – a state called aneuploidy. Aneuploidy is an important feature of many aggressive cancers. We are also interested in using the molecular knowledge of chromosome segregation to design personalised or tumour-specific therapeutic tools to tackle cancer.

Our current focus is to determine the molecular mechanics of a sub-micron sized multi-protein machine called the ‘kinetochore’.  The kinetochore assembles on the centromeric DNA of chromosomes and serves as a platform onto which themicrotubules of mitotic spindle stochastically attach.  Correct kinetochore-microtubule attachment is critical to impart the mechanical forces which pull chromosomes apart into two equal sets during cell division.

Mechanical force generation during segregation

We study how kinetochores establish microtubule attachments, withstand pulling forces, monitor defective attachments and correct them to ensure accurate chromosome segregation.  For these studies, we use high-resolution and high-throughput imaging in combination with molecular biology and computational techniques to measure and manipulate the mechanical forces that power chromosome movement.

Checkpoint signalling and biochemical composition of kinetochores

In healthy cells, incorrect kinetochore-microtubule attachments trigger a robust signal that delays the onset of chromosome segregation and prevents missegregation.  This delay is orchestrated by a sensitive spindle checkpoint mechanism whose protein members (Bubs, Mads, MPS1, AuroraB, and TAO1) are selectively recruited to kinetochores with incorrect attachments.  We investigate whether and to what extent the checkpoint protein’s roles are impaired in aneuploid tumour cells. We also employ biochemistry tools (mass spectrometry) to determine the checkpoint signalling mechanism and biochemical composition of kinetochores in healthy cells.

3 key publications

1. Draviam VM, Stegmeier F, Nalepa G, Sowa ME, Chen J, Liang A, Hannon GJ, Sorger PK, Harper JW, Elledge SJ (2007) A functional genomic screen identifies a role for TAO1 kinase in spindle-checkpoint signalling. Nat Cell Biol. 9: 556-64

2. Draviam VM, Shapiro I, Aldridge B, Sorger PK (2006) Misorientation and reduced stretching of aligned sister kinetochores promote chromosome missegregation in EB1- or APC-depleted cells. EMBO J. 25: 2814-27

3. Meraldi P, Draviam VM, Sorger PK (2004) Timing and checkpoints in the regulation of mitotic progression. Dev Cell. 7: 45-60

Page updated 21 August 2009