MYC primes a paralog synthetic lethality involving the mitochondrial translocase subunits TIMM17A and TIMM17B and N-Acetylaspartate
To identify the genes and pathways required for the survival of MYC -amplified cancers, we engineered an isogenic cell system in which transformation is driven by oncogenic MYC . Using a genome-scale CRISPR-Cas9 library, we identified the mitochondrial membrane translocase TIMM17A as uniquely essential for the survival of MYC-transformed cells. This dependency arises from MYC-driven suppression of TIMM17B , the paralog of TIMM17A . TIMM17A/B is an essential component of the TIM23 mitochondrial protein import complex, and the MYC-induced suppression of TIMM17B creates a strong dependency on TIMM17A . N-acetylaspartate supplementation rescued TIMM17A dependency in MYC -amplified cell lines, highlighting the unique and crucial role of this metabolite in the cell fitness of MYC -amplified cancers. These observations identify a paralog dependency required for the survival of a subset of MYC-driven cancers.
Authors
- Lucas Dailey (ORCID: https://orcid.org/0000-0003-3204-9565)
- Federica Piccioni (ORCID: https://orcid.org/0000-0003-1210-3210)
- Kathia E. Rodarte (ORCID: https://orcid.org/0000-0001-7608-7585)
- Brian H. Shim (ORCID: https://orcid.org/0000-0002-3032-2049)
- Hans R. Widlund (ORCID: https://orcid.org/0000-0002-7506-2447)
- Jessica A. Talamas (ORCID: https://orcid.org/0000-0002-7887-6294)
- Sydney M. Moyer (ORCID: https://orcid.org/0000-0002-2911-4058)
- Jonathan So (ORCID: https://orcid.org/0000-0001-9919-2476)
- Jonathan P. Rennhack (ORCID: https://orcid.org/0000-0001-6306-195X)
- Clary B. Clish (ORCID: https://orcid.org/0000-0001-8259-9245)
- William C. Hahn (ORCID: https://orcid.org/0000-0003-2840-9791)
- Nika N. Danial (ORCID: https://orcid.org/0000-0003-4842-1827)
- Sydney Gang (ORCID: https://orcid.org/0000-0003-0410-7262)
- David E. Root (ORCID: https://orcid.org/0000-0001-5122-861X)
- Joseph D. DeAngelo (ORCID: https://orcid.org/0000-0001-5008-0414)
- Gaia Taig (ORCID: https://orcid.org/0009-0003-5269-8551)
- John Ryan Jacob (ORCID: https://orcid.org/0000-0003-4447-6660)
- Nina Ilić (ORCID: https://orcid.org/0009-0001-3749-4601)
- Jasmine Stavridi
- Helen Wang
- Andrea Jiang (ORCID: https://orcid.org/0009-0003-0772-7093)
- Melis A. Akinci (ORCID: https://orcid.org/0000-0003-0104-9095)
- Sehyun Oh (ORCID: https://orcid.org/0009-0003-0366-2413)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-11-06
- DOI
- https://doi.org/10.1126/sciadv.aej2662
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Cancer Center
- National Institutes of Health