Defects in DDR lead to genomic instability that may trigger tumorigenesis. Genomic instability can manifest as a higher rate of acquisition of gross numerical or structural changes in the chromosomes, known as chromosomal instability (CIN). CIN is associated with the development of resistance to treatments, it is clear that it is recurrently elevated after DDR components’ inhibition. That is why, although it is challenging, to think of strategies that induce cell death without generating abrupt and acute changes in CIN levels. When evaluating the mechanisms of cell death after the elimination of a DNA polymerase (pol eta), we found that the depletion of pol exacerbates the cell death caused by DNA damaging agents without causing a concomitant increase in CIN. This response happens because, in the absence of pol eta, cells cannot complete DNA replication and are more efficiently arrested in S phase. Soon after the DNA damaging challenge, cells depleted from pol eta display augmented DSBs that persist over time. DSBs are followed by the accumulation of massive regions of ssDNA and pan-nuclear phosphorylation of histone H2AX, which has been shown to correlate with a commitment to cell death. We also found evidence of RPA exhaustion, a marker that characterizes cell death in S phase. Such results suggest that the modulation of specific DDR effectors could selectively promote cell death in S phase, preventing CIN augmentation, a concept that may be relevant in clinical settings.