Long-term mitotic DNA damage promotes chromokinesin-mediated missegregation of polar chromosomes in cancer cells

Abstract

DNA damage response (DDR) during interphase involves active signalling and repair to ensure genomic stability. However, how mitotic cells respond to DNA damage remains poorly understood. Supported by correlative live-/fixed-cell microscopy analysis we found that mitotic cells exposed to several cancer chemotherapy compounds acquire and signal DNA damage, regardless of how they interact with DNA. In-depth analysis upon long-term DNA damage during mitosis revealed a spindle assembly checkpoint (SAC)-dependent, but DDR-independent, mitotic delay. This delay was due to the presence of misaligned chromosomes that ultimately satisfy the SAC and missegregate, leading to micronuclei formation. Mechanistically, we show that long-term mitotic DNA damage specifically stabilizes kinetochore-microtubule attachments in cancer cells, causing the missegregation of polar chromosomes due to the action of arm-ejection forces by chromokinesins. Overall, these findings unveil that long-term therapeutic DNA damage regimens contribute to genomic instability through a surprising link between the stabilization of kinetochore-microtubule attachments and chromokinesin-mediated missegregation of polar chromosomes in cancer cells.

Genetic Studies Highlight the Role of TET2 and INO80 in DNA Damage Response and Kidney Disease Pathogenesis

“…Altered DNA damage response (DDR) during mitosis can lead to the accumulation of damaged DNA and chromosome mis-segregation 32, 35 . We observed a higher level of phosphorylated checkpoint kinase 2 (p-CHK2), which is a marker of the DDR, in doxorubicin-treated cells isolated from the kidneys of Six2 Cre Tet2 f/f mice when compared with those in doxorubicin-treated control cells isolated the kidneys of Six2 Cre mice (Figure 5D).…”