Homologous recombination (HR) deficiency due to loss of BRCA function in cells leads to a propensity to the genesis of different types of cancer. Conversely, such HR deficiency is exploited to cause synthetic lethality (SL) or tumor-specific cell death in BRCA-deficient cancers. Such a synthetic lethality can be achieved by using drugs such as PARP inhibitors (PARPi) that prompt the accumulation of substrates for HR, e.g., DNA double-strand breaks (DSBs), which cannot be repaired in HR deficient cells. The trigger for SL in BRCA deficient cells treated with PARPi is intimately associated with acute DNA replication stress. In contrast, we have recently reported that BRCA1-deficient cells can be killed in a manner independent from such an S phase-associated stress. We found that inhibition of PLK1, an M-phase master kinase, causes SL in BRCA1 deficient models in a manner that does not augment parameters of DNA replication stress. Instead, BRCA1-deficient cells treated with PLK1i aggregate into multinucleated structures that suggest M phase’s role in the SL triggered by PLKi. To get insight into such a DNA replication stress-independent SL mechanism, we will systematically monitor chromosome segregation, and other M phase parameters (multipolar mitoses, chromosome bridges, and lagging chromosomes resolution) will be discussed in depth during the presentation of results.