MYC primes a paralog synthetic lethality involving the mitochondrial translocase subunits TIMM17A and TIMM17B and N-Acetylaspartate.

MYC-amplified cancer cells are uniquely dependent on the mitochondrial translocase subunit TIMM17A, driven by MYC-mediated suppression of its paralog TIMM17B.

• Why it matters: Identifying vulnerabilities in MYC-amplified cancers addresses the need to find genes and pathways that these tumors require for survival.
• What they did: In an isogenic CRISPR-Cas9 genome-scale screen of MYC-driven transformed cells, TIMM17A emerged as uniquely essential; MYC suppressed TIMM17B, and N-acetylaspartate supplementation rescued TIMM17A dependency.
• The result: The TIMM17A/TIMM17B paralog dependency, linked to the TIM23 mitochondrial protein import complex, is supported by metabolite rescue, suggesting N-acetylaspartate can restore fitness in MYC-amplified lines.

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