How Cells Handle DNA Breaks during Mitosis: Detection, Signaling, Repair, and Fate Choice

Abstract

Mitosis is controlled by a complex series of signaling pathways but mitotic control following DNA damage remains poorly understood. Effective DNA damage sensing and repair is integral to survival but is largely thought to occur primarily in interphase and be repressed during mitosis due to the risk of telomere fusion. There is, however, increasing evidence to suggest tight control of mitotic progression in the incidence of DNA damage, whether induced in mitotic cells or having progressed from failed interphase checkpoints. Here we will discuss what is known to date about signaling pathways controlling mitotic progression and resulting cell fate in the incidence of mitotic DNA damage.

Keywords: DNA damage; DNA repair; cancer; cell fate; mitosis.

Figure 1

Acentric chromosomes resulting from DNA breaks or replication stress could lead to chromosomal instability if incorrectly segregated. We propose that multiprotein complexes made of DDR and SAC proteins form to tether broken chromosome fragments and facilitate accurate chromosome segregation. Image created using BioRender.

Figure 2

Summary of documented interplay between the DDR and SAC. DDR effectors ATM/ATR and downstream Chk1 have all been demonstrated as playing a role in SAC control, both in the unperturbed cell cycle and cells exposed to DNA damage.

Figure 3

Interaction of BubR1 and PIDD at centrosomes. In the incidence of supernumerary centrosomes, PIDD interacts with RAIDD and assembles to PIDDosome resulting in either cell death or senescence depending on p53 status. Image created using BioRender.