Elucidating the molecular and epigenetic basis of centromere instability and premature sister chromatid cohesion separation

Abstract

Aneuploidy and numerical chromosome instability are hallmarks in solid tumors, which could be cause by elevated mitotic chromosome missegregation. The centromere is the specialized chromosomal domain responsible for assembling the kinetochore, which attaches microtubules to orchestrate chromosome movements. In atypical lipomas and well-differentiated liposarcomas (ALP-WDLPS) cells, chromosome rearrangements result in chromosome fragments that lack the endogenous centromere. Yet, a neocentromere can form on non-centromeric region in supernumerary ring or marker chromosomes. In other cases, neocentromeres may be formed with the inactivation of endogenous centromeres without any loss of sequence. Moreover, overexpression of kinetochore proteins can result in ectopic kinetochore formation in cancers. In addition, sister chromatid cohesion has to be established in S phase, and maintained until anaphase. Components of the cohesin ring and cohesion establishment factors are mutated at high frequency in colorectal cancers. Here I will discuss the epigenetic regulation of centromere activity and sister chromatid cohesion, and their potentials as therapeutic cancer targets.