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Madhusudhan Srinivasan

Wellcome Trust Career Development Fellow

Eukaryotic Chromosome segregation

The instructions for life are carried in long molecules of DNA called chromosomes that must be accurately copied and shared out every time a cell divides. Precise division of the duplicated chromosomes ( sister chromatids) between daughter cells is possible because they are held together from the moment they are produced until they separate and move to opposite poles of a dividing cell. This tight association of sister chromatids is called Sister Chromatid Cohesion (cohesion) and is mediated by a ring-shaped protein complex called cohesin. Sister chromatids are stably trapped inside this cohesin ring until just before cell division, when cleavage of the cohesin rings allows separation of the sister chromatids. Cohesin therefore, is essential for orderly segregation of chromosomes and perturbation of its function can drive the formation of human cancers and developmental disorders. Despite the fundamental importance of cohesion, the mechanisms that generate cohesion remain enigmatic. This constitutes a major gap in our understanding of cells and human diseases.

Our long-term goal is to define the molecular mechanism of cohesion establishment and through this understand the fundamental process that underpins eukaryotic chromosome segregation. To do this, we use a multidisciplinary approach that combines genetics, cell biology, molecular biology, biochemistry, and biophysics. Key methodologies we use include in vitro biochemical assays and in vitro single molecule imaging, single particle tracking in live cells, super-resolution ultrastructural imaging, and high-throughput sequencing based methods (ChIP-seq, Hi-C etc).