CIN-independent cell death in S phase induced by pol eta depletion

SIRI, SEBASTIÁN OMAR; GOTTIFREDI, VANESA; OKRAINE VERONICA YIOVANA; FEDERICO, MARÍA BELÉN

Buenos Aires

Simposio; Buenos Aires Breast Cancer Symposium BA-BCS2021; 2021

Defects in DDR lead to genomic instability that maytrigger tumorigenesis. Genomic instability can manifest asa higher rate of acquisition of gross numerical or structuralchanges in the chromosomes, known as chromosomalinstability (CIN). CIN is associated with the developmentof resistance to treatments, it is clear that it is recurrentlyelevated after DDR components’ inhibition. That is why,although it is challenging, to think of strategies that inducecell death without generating abrupt and acute changes inCIN levels. When evaluating the mechanisms of cell deathafter the elimination of a DNA polymerase (pol eta), wefound that the depletion of pol exacerbates the cell deathcaused by DNA damaging agents without causing a concomitant increase in CIN. This response happens because,in the absence of pol eta, cells cannot complete DNAreplication and are more efficiently arrested in S phase.Soon after the DNA damaging challenge, cells depletedfrom pol eta display augmented DSBs that persist overtime. DSBs are followed by the accumulation of massiveregions of ssDNA and pan-nuclear phosphorylation ofhistone H2AX, which has been shown to correlate witha commitment to cell death. We also found evidence ofRPA exhaustion, a marker that characterizes cell deathin S phase. Such results suggest that the modulation ofspecific DDR effectors could selectively promote cell deathin S phase, preventing CIN augmentation, a concept thatmay be relevant in clinical settings