Crucial checkpoints detect DNA damage and arrest the cell cycle, allowing cells to repair DNA or undergo apoptosis. These responses maintain a stable genome. DNA damage checkpoints are also exploited therapeutically to kill proliferative tumor cells. However, many tumors eventually become resistant to death by DNA damage. Resistance is associated with mutations in DNA checkpoint responders, and/or inactivity of canonical checkpoint regulators. How such resistant cells can proliferate and survive DNA damage is poorly understood.
Cells lacking elements of the DNA damage response are not limited to pathological conditions. The endocycle, a conserved cell cycle in which cells alternate between S and G phases, increasing in ploidy without increasing in cell number, is known to silence elements of the DNA damage response. However, many endocycled cells do not divide. In the Drosophila rectum, we previously found endocycled papillar cells re-enter mitosis as polyploid cells.
Here, we show that papillar cells also acquire radiation-resistance during the endocycle, allowing us to study the effects of a silenced DNA damage response on subsequent mitosis. We find papillar cells accumulate DNA breaks and acentric DNA fragments during endocycles. Rather than undergo high fidelity DNA repair prior to mitosis, papillar cells divide with broken DNA. Amazingly, papillar cells employ an active mechanism to properly segregate acentric DNA fragments during anaphase, enabling cell survival and proper organogenesis. We find that this response requires the Fanconi Anemia FANCD2/FANCI heterodimer and frequent partner Bloom helicase. Lack of FANCD2 results in failure to incorporate acentric DNA into daughter nuclei, leading to micronuclei. This causes papillar cell death and formation of a non-functional organ. Interestingly, this response is independent of canonical DNA damage response proteins. Our work sheds light on a non-canonical chromosome patching mechanism used to accurately segregate broken acentric DNA during mitosis. We speculate that this response may be shared by other cells lacking an intact DNA damage response, such as radiation-resistant tumor cells.