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

Year: 2026

Type: article

Abstract: 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.

Source: Science Advances

DOI: 10.1126/sciadv.aej2662

Institutions: Broad Institute, Harvard University, Dana-Farber Cancer Institute, Brigham and Women's Hospital

Language: English

Topic: Mitochondrial Function and Pathology

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,500

Funders: National Cancer Center, National Institutes of Health, National Cancer Institute

Award: The Dana-Farber Cancer Institute Cancer Target Discovery and Development Center

OpenAlex ID: W7225380505