Homologous recombination promotes non-immunogenic mitotic cell death upon DNA damage

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Double-strand breaks (DSBs) are critical DNA lesions that can lead to cell death, known as mitotic catastrophe.
• Mitotic catastrophe is a complex process that acts as a tumor suppressor mechanism by eliminating damaged cells during or after cell division.

Purpose of the Study:

• To elucidate how cell cycle-regulated DNA repair pathways influence the distinct outcomes of mitotic catastrophe.
• To investigate the relationship between DNA repair, cell death, and immune signaling following genome damage.

Main Methods:

• Single-cell analysis using extended live imaging.
• Induction of double-strand breaks in cells during different phases of the cell cycle (S, G2, G1).
• Manipulation of specific DNA repair pathways, including homologous recombination, non-homologous end joining, and microhomology-mediated end joining.

Main Results:

• Passage of unresolved homologous recombination intermediates into mitosis promotes immediate, non-immunogenic intrinsic apoptosis.
• DNA repair mechanisms in G1 cells (non-homologous end joining, microhomology-mediated end joining, single-strand annealing) allow cell cycle completion with aberrant division, leading to delayed extrinsic lethality and interferon production.
• Targeting these G1 repair pathways shifts cell death towards mitotic death, while suppressing mitotic death enhances interferon production.
• Homologous recombination suppresses interferon production by promoting mitotic lethality.

Conclusions:

• A temporal hierarchy of DNA repair, influenced by the cumulative DSB load, predicts the outcome of mitotic catastrophe.
• Cell cycle-dependent DNA repair choice dictates cell fate, impacting both cell death type and subsequent immune signaling.
• Understanding these pathways offers insights into cancer suppression and potential therapeutic strategies targeting DNA repair and immune responses.