Seminars

Calvin Tiengwe, Department of Life Sciences, Imperial College London

Iron-dependent control of transferrin receptor expression in Trypanosoma brucei

Iron is an essential co-factor for many enzymatic reactions, but also potentially very destructive at high concentrations. Consequently, cells exert a tight control on intracellular iron levels. A prominent control nexus involves iron regulatory RNA binding proteins (RBP) binding iron responsive elements to modulate stability of mRNAs encoding major components of the iron-acquisition pathway, such as the transferrin receptor. This process has been studied in many systems revealing unique mechanisms in each, yet remains relatively poorly understood in T. brucei, a “neglected” pathogen that causes African sleeping sickness in humans and livestock. To understand how T. brucei controls expression of its transferrin receptor (TbTfR), we performed genome-wide transcriptomic and proteomic studies to identify parasite-specific iron-responsive factors.

The first half of this talk will cover functional characterisation of an RBP as a novel post-transcriptional regulator of TbTfR expression. In the second half, I discuss our initial attempts to use orthogonal organic phase separation (OOPS), a method first described by the group of Kathryn Lilley, to comprehensively capture the RBPome of bloodstream stage trypanosomes. Our ultimate goal is to characterise RNA-protein dynamic interactions involved in iron homeostasis in T. brucei.

Host: Atlanta Cook

Camilla Björkegren, Karolinska Institutet, Sweden

Wellcome Centre Seminar - The Smc5/6 complex, DNA supercoiling and chromosome segregation

Cohesin, condensin and the Smc5/6 complex (Smc5/6) belong to the family of Structural Maintenance of Chromosome (SMC) protein complexes. By regulating chromosome structure and dynamics, these complexes influence chromosome replication, segregation, repair, and transcription. Cohesin is most well-known for its essential role in sister chromatid cohesion, condensin for its function in chromosome condensation, and Smc5/6 was first shown to control DNA repair and recombination. Chromosome segregation also fails in unchallenged cells lacking Smc5/6, but the reason for this remains mostly unknown.

To reveal the function of Smc5/6, we analyze the Saccharomyces cerevisiae complex in vivo and in vitro. The investigations show that the chromosomal association of Smc5/6 is dynamic and regulated by multiple factors, including chromosome length, sister chromatid entanglement, and transcription of convergently oriented genes. We also find that the purified complex promotes DNA decatenation by Top2, and compacts supercoiled DNA in a process that depends on ATP hydrolysis. Taken together, the results suggest that Smc5/6 function is linked to the level of supercoiling in chromosomal DNA. Results from these investigations, and their implications for the understanding of Smc5/6 function and supercoiling of the replicated genome, will be presented and discussed.

Host: Adele Marston

Claude Prigent, French National Centre for Scientific Research, Institute of Genetics and Development of Rennes

Wellcome Centre Seminar - Aurora-A : much more than a mitotic kinase

Aurora-A has been discovered as a centrosome protein kinase. Its activity is necessary for mitosis, it controls the maturation of centrosomes, the G2 / M transition, the assembly of the bipolar spindle, the spindle assembly checkpoint, the assembly of the central spindle, etc. Aurora-A is also an oncogene and is overexpressed in many epithelial cancers. This over-expression is correlated with the aggressiveness of cancer. Claude Prigent is currently investigating how overexpression of Aurora-A confers an advantage on cancer cells.

Host: Bill Earnshaw