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

Oncogene volume 39, pages 3952–3964 (2020)Cite this article

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A Correction to this article was published on 12 October 2023

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Abstract

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 cell death. However, their molecular triggers and the relative timing of these events have not been fully elucidated. Here, we report that 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 exposure of template single-stranded DNA (ssDNA), which indicate severe replication stress, accumulate and such events are followed by cell 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, pan-nuclear ssDNA/γH2AX, S-phase arrest, and cell death are all attenuated by MRE11 nuclease knockdown. Such results suggest that unscheduled MRE11-dependent activities at replicating DNA selectively trigger cell death, but not CIN. Together these results show that pol η-depletion promotes a type of cell death that may be attractive as a therapeutic tool because of the lack of CIN.

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Fig. 1: Pol η depletion causes CIN-independent cell death.
Fig. 2: Pol η depletion causes cell cycle arrest and augments DSB accumulation independently from FANCD2-mediated repair.
Fig. 3: DSBs accumulation precedes acute replication stress in pol η-depleted cells.
Fig. 4: RPA down-modulation augments pan-nuclear single-stranded DNA (ssDNA) accumulation, and cell death in UV-irradiated pol η-depleted cells.
Fig. 5: MRE11 depletion prevents DSBs and pan-nuclear ssDNA accumulation in UV-irradiated pol η-depleted cells.
Fig. 6: MRE11 depletion alleviates the S-phase arrest and cell death, but increases the G2/M arrest of UV-irradiated pol η-depleted cells.
Fig. 7: The role of unscheduled MRE1-mediated replication transactions in the cell death of pol η-depleted samples.

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Acknowledgements

We would like to thank Professors AR Lehmann (University of Sussex), for the gift of XPV cells. We also thank Carlos Menck at the University of Sao Paolo and all the members of the Gottifredi laboratory for fruitful discussions. The excellent support of Andres H. Rossi and Anabel Alvaréz Julia in the microscopy and tissue cultures facilities is acknowledged. This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) grant number PICT 2015-1217, Instituto Nacional del Cancer (INC)—“Asistencia Financiera a proyectos de investigación de cáncer de origen nacional III to VG and the German Cancer Aid, Priority Program “Translational Oncology” 70112504 and by the Deutsche Forschungsgemeinschaft (DFG, Research Training Group 2544) to LW. MBF, SOS, NLC, NSP, JM, and MBdlV were supported by fellowships from CONICET and ANPCyT. VG is a researcher from CONICET and was supported by the Friedrich Wilhelm Bessel from Alexander von Humboldt Foundation.

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  1. These authors contributed equally: Sebastián Omar Siri, Nicolás Luis Calzetta

Authors and Affiliations

  1. Cell Cycle and Genomic Stability laboratory. Fundación Instituto Leloir. CONICET, Av. Patricias Argentinas 435, 1405, Buenos Aires, Argentina

    María Belén Federico, Sebastián Omar Siri, Nicolás Luis Calzetta, Natalia Soledad Paviolo, María Belén de la Vega, Julieta Martino, María Carolina Campana & Vanesa Gottifredi

  2. Department of Obstetrics and Gynecology, Ulm University, D-89075, Ulm, Germany

    Lisa Wiesmüller

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VG conceived the study; MBF and VG designed the experiments; MBF, SOS, NLC, NSP, MBdlV, JM, and MCC performed experiments; MBF, SOS, NLC, JM, and VG interpreted the data; MBF and SOS designed and generated the figures with the help of LW and VG; VG wrote the paper and all authors edited it; LW and VG supervised the project.

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Federico, M.B., Siri, S.O., Calzetta, N.L. et al. Unscheduled MRE11 activity triggers cell death but not chromosome instability in polymerase eta-depleted cells subjected to UV irradiation. Oncogene 39, 3952–3964 (2020). https://doi.org/10.1038/s41388-020-1265-9

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