DNA-Damage Response during Mitosis Induces Whole-Chromosome Missegregation

Abstract

Many cancers display both structural (s-CIN) and numerical (w-CIN) chromosomal instabilities. Defective chromosome segregation during mitosis has been shown to cause DNA damage that induces structural rearrangements of chromosomes (s-CIN). In contrast, whether DNA damage can disrupt mitotic processes to generate whole chromosomal instability (w-CIN) is unknown. Here we show that activation of the DNA damage response (DDR) during mitosis selectively stabilizes kinetochore-microtubule (k-MT) attachments to chromosomes through Aurora-A and Plk1 kinases, thereby increasing the frequency of lagging chromosomes during anaphase. Inhibition of DDR proteins, ATM or Chk2, abolishes the effect of DNA damage on k-MTs and chromosome segregation, whereas activation of the DDR in the absence of DNA damage is sufficient to induce chromosome segregation errors. Finally, inhibiting the DDR during mitosis in cancer cells with persistent DNA damage suppresses inherent chromosome segregation defects. Thus, DDR during mitosis inappropriately stabilizes k-MTs creating a link between s-CIN and w-CIN.

DNA damage response during mouse oocyte maturation

“…In cancer cells when DNA damage is induced in mitosis, DDR selectively stabilizes microtubule-kinetochore attachments through AURKA and PLK1 kinases, which increases the frequency of lagging chromosomes in anaphase. 33 Thus, this phenomenon appears to operate in MI when homologous chromosomes segregate. An interesting question for future investigation is whether the increased level of DSBs in GV-stage oocytes from both older human females or mice 17 contributes to the higher incidence of aneuploidy associated with age; loss of cohesion is the primary source.…”

Role of chromosomal instability in cancer progression

“…DNA damage can also lead to missegregation of damaged chromosomes and chromosome fragments at mitosis (Kaye et al 2004). A more subtle effect of an activated DNA damage response in mitosis was also recently shown to impair normal chromosome attachment error correction machinery, resulting in merotelic attachments and aneuploidy (Bakhoum et al 2014). Defects in the prevention of genome re-replication have additionally been shown as a non-mitotic route to changes in centromere number, albeit only in a yeast system to date (Hanlon & Li 2015).…”

ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response

“…S/A, S157A/S376A; S/D, S157D/ S376D; S/E, S157E/S376E. ined whether PALB2 phosphorylation at Ser-157 and Ser-376 are specific to interphase cells, as aberrant activation of the DDR during mitosis appears to promote chromosome instability (37)(38)(39). To this end we harvested mitotic cells by use of the microtubule-depolymerizing drug nocodazole, and compared the phosphorylation status of PALB2 in an asynchronized cell population in response to 10 Gy IR (Fig.…”