Unscheduled MRE11 activity triggers cell death but not chromosome instability in polymerase eta-depleted cells subjected to UV irradiation

SIRI, SEBASTIÁN OMAR*; DE LA VEGA, MARÍA BELÉN; FEDERICO, MARÍA BELÉN; WIESMÜLLER, LISA; PAVIOLO, NATALIA SOLEDAD; CAMPANA, MARÍA CAROLINA; CALZETTA, NICOLÁS LUIS*; MARTINO, JULIETA; GOTTIFREDI, VANESA

ONCOGENE

NATURE PUBLISHING GROUP

Año: 2020 vol. 39 p. 3952 - 3964

0950-9232

The elimination of DNA polymerase eta (pol η) causes discontinuous DNA elongation and fork stalling in UV-irradiated cells.Such alterations in DNA replication are followed by S-phase arrest, DNA double-strand break (DSB) accumulation, and celldeath. However, their molecular triggers and the relative timing of these events have not been fully elucidated. Here, we reportthat DSBs accumulate relatively early after UV irradiation in pol η-depleted cells. Despite the availability of repair pathways,DSBs persist and chromosome instability (CIN) is not detectable. Later on cells with pan-nuclear γH2AX and massive exposureof template single-stranded DNA (ssDNA), which indicate severe replication stress, accumulate and such events are followed bycell death. Reinforcing the causal link between the accumulation of pan-nuclear ssDNA/γH2AX signals and cell death,downregulation of RPA increased both replication stress and the cell death of pol η-deficient cells. Remarkably, DSBs, pannuclearssDNA/γH2AX, S-phase arrest, and cell death are all attenuated by MRE11 nuclease knockdown. Such results suggestthat unscheduled MRE11-dependent activities at replicating DNA selectively trigger cell death, but not CIN. Together theseresults show that pol η-depletion promotes a type of cell death that may be attractive as a therapeutic tool because of the lackof CIN.