The mitotic origin of chromosomal instability

Abstract

Summary Chromosomal instability (CIN) is a common feature of most human neoplasms and was defined, in a seminal study by Vogelstein and colleagues [1], as persistently elevated rates of whole chromosome mis-segregation. Since then, it was shown that certain errors in mitosis, including defects in the spindle assembly checkpoint [2], sister chromatid cohesion [3], kinetochore-microtubule (kMT) attachments [4,5], and centrosome number [6] can cause chromosome mis-segregation in the form of merotelically attached anaphase lagging chromosomes — chromosomes that lag behind at the spindle equator while all the other chromosomes move toward the spindle poles [7] (Figure 1A). A recent study has suggested that pre-mitotic replication stress generates partially replicated chromosomes during mitosis, and that this results in both numerical and structural chromosome abnormalities through the formation of chromosome bridges and acentric chromosome fragments during anaphase [8]. To determine whether whole chromosome instability in cancer cells is caused by defects originating in mitosis (lagging chromosomes) or from ones originating pre-mitotically (chromatin bridges and acentric fragments), we compared a variety of CIN+ to CIN- cells to determine the types of segregation defects that phenotypically distinguish CIN+ from CIN- cells and whose abrogation can rescue whole chromosomal instability.