1/Delighted to announce the newest paper from our lab, “Homologous recombination promotes non-immunogenic mitotic cell death upon DNA damage”, is out today in @naturecellbiology.bsky.social, https://www.nature.com/articles/s41556-024-01557-x.
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Congrats @thecesarelab.bsky.social and @szmyd-radoslaw.bsky.social. It’s been great to see this work develop, and even better to finally see it out in print! 🥂🍻
2/This work was led by out exceptionally talented post-doc @szmyd-radoslaw.bsky.social and co-supervised by @radoncdocgee.bsky.social. Long🧵below with images/movies are shared from the open access paper.
TL;DR double strand break repair determines the manner in which irradiated cells die.
3/For this project, Radek performed single cell analysis from long-duration live imaging (up to 5 days) of three-colour FUCCI cells treated with a single dose of 2 to 20 Gy ionizing radiation (IR). This allowed us to correlate cell cycle phase at IR and cell outcome.
4/As expected, p53 wildtype cells arrested following IR. Damaged human p53 mutant cancer cells, or HPV E6E7 expressing primary fibroblasts, however, continued cell cycle progression. Interestingly, cell outcome was a function of cell cycle phase at damage induction.
5/Even with clinical ablative radiotherapy dosages (8 – 20 Gy), G1 damaged cells largely survived the first cell division (i.e. mitosis). But did so at the expense of chromosome segregation errors. With 8+ Gy, G1 damaged cells eventually died after ≥ 1 aberrant cell divisions.
6/Conversely, S/G2 damaged cells were far more IR sensitive. Sub-ablative IR readily killed S/G2 damaged cells in the immediately following mitosis, and ablative IR removed all S/G2 damaged cells in first mitotic attempt. Thus, damaged G1 and S/G2 cells responded differently.
7/Mitotic death with S/G2 IR correlated with extended mitotic arrest. We found mitotic lethality was depended on persistent spindle assembly checkpoint (SAC) activation and inhibiting the SAC with Reversine completely suppressed mitotic lethality following IR.
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TL;DR double strand break repair determines the manner in which irradiated cells die.