Cas12a-based combinatorial knockout screens define the genetic architecture of the DNA damage response.

Cas12a combinatorial knockout screens in cancer-relevant DDR genes reveal high-confidence positive and negative gene-gene interactions, including synthetic lethality between REV1-Pol ζ and MCM8-MCM9-HROB.

• Why it matters: The DDR network’s genetic architecture and cross-pathway wiring are incompletely mapped, limiting how well vulnerabilities in mutation-defined tumors can be identified.
• What they did: Using Cas12a, the study disrupts 233 frequently mutated DDR genes singly and in pairwise combinations, then measures phenotypes under unperturbed cell growth to call interaction effects.
• The result: Synthetic lethal links are found between REV1-Pol ζ and MCM8-MCM9-HROB, between Fanconi anemia genes and mitotic DNA repair genes, and between SMARCAL1 and FANCM components, enabling mutation-linked therapeutic targeting.

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