Probing chromosome segregation using genetic and chemical perturbations

Despite the continuous recent efforts, cancer remains one of the deadliest diseases worldwide (Bray et al. 2018). Therefore, it is essential to understand the mechanisms of tumor initiation and progression in order to discover new ways to improve cancer therapy. Here, I focused on identifying mechanisms that could potentially contribute to tumor initiation as well as understanding the way of action of chemotherapeutic regimens with the goal to improve their specificity. This thesis is divided into three parts; in the first part, we investigated how defects in the spindle assembly checkpoint (SAC; cellular mechanism that ensures faithful segregation of the genetic material) can contribute to the erroneous segregation of chromosomes in mitosis. In the second part, we focused on how replication stress can impact chromosome segregation and thus chromosomal stability. In the third and last part, we discovered a potential mechanism that cancer cells use to resist treatment

Mild replication stress causes chromosome mis-segregation via premature centriole disengagement

Replication stress, a hallmark of cancerous and pre-cancerous lesions, is linked to structuralchromosomal aberrations. Recent studies demonstrated that it could also lead to numericalchromosomal instability (CIN). The mechanism, however, remains elusive. Here, we showthat inducing replication stress in non-cancerous cells stabilizes spindle microtubules andfavours premature centriole disengagement, causing transient multipolar spindles that lead tolagging chromosomes and micronuclei. Premature centriole disengagement depends on theG2 activity of the Cdk, Plk1 and ATR kinases, implying a DNA-damage induced deregulationof the centrosome cycle. Premature centriole disengagement also occurs spontaneously insome CIN+cancer cell lines and can be suppressed by attenuating replication stress. Finally,we show that replication stress potentiates the effect of the chemotherapeutic agent taxol, byincreasing the incidence of multipolar cell divisions. We postulate that replication stress incancer cells induces numerical CIN via transient multipolar spindles caused by prematurecentriole disengagement