Our group is focusing on the cellular fate of chromosome fusion.
The ends of linear chromosomes are protected from being recognized as DNA damage by telomeres. As telomeric regions get shorter during each somatic cell division cycle, they eventually reach a critical length – upon which telomeric ends no longer serve their protective function. This leads to permanent cell cycle arrest, a phenomenon called replicative senescence, through activation of various DNA damage response (DDR) mechanisms. When cells possess defects in DDR, they can bypass senescence and keep dividing while telomeres get further shortened. This final stage, called telomere crisis, is characterized by massive cell death and accumulation of chromosome instability, the latter of which is a well-accepted driving force of tumorigenesis (Figure 1).
Chromosome fusion is proposed to be the underlying cause of both cell death and chromosome instability during telomere crisis, however the detailed mechanisms remain elusive. The goal of our current projects is to understand how chromosome fusions can result in diverse cellular fates during telomere crisis (Figure 2).
We have recently developed a new tool, called Fusion Visualization system for the Xp sister chromatid fusion (FuVis-XpSIS). The FuVis relies on an artificial DNA cassette integrated into the Xp subtelomere. The cassette has been designed so that the CRISPR/Cas9-mediated DSB of the cassette generates a single sister chromatid fusion concomitantly with mCitrine expression (Figure 3). With this new technique, we are analyzing the fate of a specific single sister chromatid fusion in cancer cells.