Extended G2/M arrests lead to aberrant mitoses and cell death due to excessive securin

Abstract

The stochastic nature of DNA damage dictates various scenarios of stress survival among different cells. We used time-lapse microscopy to perform single-cell level analyses of yeast populations with double-stranded DNA breaks and nonfunctional telomeres. Activation of the DNA damage signalling resulted in a broad distribution in the duration of G2/M arrests. Strikingly, the longer arrests correlated with aberrant mitoses caused by mis-coordination of nuclear division and cytokinesis, leading to cell death. Chk1-dependent phosphorylation of securin, an inhibitor of sister chromatid separation in mitosis, was responsible for this phenomenon. Securin progressively accumulated during G2/M arrests, leading to grossly delayed or missed nuclear divisions. This phenotype could be suppressed by slowing down the progression of mitotic exit via LTE1 deletion. Lowering securin levels also partially supressed the DNA damage-induced aberrant mitoses but resulted in an increase in aneuploidy during normal growth. Our results demonstrate that in cells taking too long to complete DNA repair, the DNA damage checkpoint promotes aberrant mitoses and cell death, thereby eliminating cells with a higher chance of genomic instability. This mechanism in microbial populations might parallel the senescence program in mammals where long cell cycle arrests become irreversible and also lead to cell death. IMPORTANTO_LIManuscripts submitted to Review Commons are peer reviewed in a journal-agnostic way. C_LIO_LIUpon transfer of the peer reviewed preprint to a journal, the referee reports will be available in full to the handling editor. C_LIO_LIThe identity of the referees will NOT be communicated to the authors unless the reviewers choose to sign their report. C_LIO_LIThe identity of the referee will be confidentially disclosed to any a filiate journals to which the manuscript is transferred. C_LI GUIDELINESO_LIFor reviewers: https://www.reviewcommons.org/reviewers C_LIO_LIFor authors: https://www.reviewcommons.org/authors C_LI CONTACTThe Review Commons office can be contacted directly at: office@reviewcommons.org