Project title: A molecular study of mechanisms that drive aneuploidy in cancers
Summary: During cell division, chromosomes attach to microtubules emanating from opposite ends of the spindle through a multiprotein structure - the kinetochore - so that sister chromatids can be separated and equally partitioned into two daughter cells. Inappropriate kinetochore-microtubule attachment can cause aneuploidy, which is commonly seen in various cancer cells. Kinetochore is a large protein assembly whose inner layer assembles on the centromere and the outer layer attaches to microtubules. The core component of the outer layer is the KMN complex, which is consisted of Knl1 complex, Ndc80 complex and Mis12 complex. The Ndc80 complex is the primary microtubule receptor at the kinetochore. The affinity of Ndc80 complex for microtubules can be regulated by Aurora B mediated phosphorylation of Nuf2 and Ndc80 subnuits. Besides Ndc80, other outer kinetochore proteins such as the Astrin:SKAP and Ska complexes are also involved in controlling and maintaining the correct kinetochore-microtubule attachment. The aim of my project is two-fold: first, to strengthen our molecular understanding of how these molecules interact with each other, sense chromosome-microtubule attachment status and ensure that chromosome segregation begins only after the proper attachment of chromosomes completion. Second, analyze the consequence of kinetochore-microtubule attachment defects in spindle orientation, using Astrin:SKAP and Ndc80-Nuf2 complexes as molecular probes, to better understand how cells prevent chromosomal instability and errors in the plane of division and tissue organisation, seen in cancers.