Identification of novel CENP-A maintenance mechanisms

Abstract

"In this thesis I will present my work on the maintenance and stability of centromeric CENP-A. The centromere is essential for accurate segregation of sister chromatids as it forms the site of attachment to microtubules emanating from the mitotic spindle. The position, its function and inheritance of the centromere is dependent on the histone H3 variant CENP-A. The assembly of CENP-A nucleosomes at the centromere occurs during early G1 in humans, which implies that cells divide with half the maximum pool of CENP-A nucleosomes assembled due to replicative dilution. We know that CENP-A nucleosomes are stably inherited from the moment they are assembled, however this stability is not intrinsic to the CENP-A nucleosomes and is subject to regulation. CENP-A nucleosomes can be assembled outside of the centromere, e.g. by the overexpression of CENP-A. This revealed that CENP-A nucleosomes outside of the centromere have a rate of turnover that is much faster than at the centromere. We now know that CENP-A stability is maintained by several factors including the constitutive centromere associated network (CCAN) protein CENP-C that can directly interact with CENP-A nucleosomes. "