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Peer-reviewedCC BY-NC 4.0Science Advances

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

  • Sydney M. Moyer1,2
  • Nina Ilic1,2
  • Sydney Gang1
  • Lucas Dailey2
  • Sehyun Oh1,3
  • Jasmine Stavridi1
  • Gaia Taig1
  • Kathia E. Rodarte1,2
  • Joseph D. DeAngelo1
  • Andrea Jiang1
  • Brian H. Shim1,2
  • Jonathan P. Rennhack1,2
11 more authors
  • John R. Jacob1,2
  • Melis A. Akinci1
  • Jonathan So1,2
  • Helen Wang1
  • Federica Piccioni2
  • Jessica A. Talamas1,2
  • Hans R. Widlund4
  • David E. Root2
  • Clary B. Clish2
  • Nika N. Danial1,3
  • William C. Hahn1,2
4 affiliations
  1. 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
  2. 2Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
  3. 3Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02115, USA.
  4. 4Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
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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.

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Cite

BibTeXRIS
BibTeX
@article{moyer2026primes,
  title = {{MYC primes a paralog synthetic lethality involving the mitochondrial translocase subunits TIMM17A and TIMM17B and N-Acetylaspartate}},
  author = {Sydney M. Moyer and Nina Ilic and Sydney Gang and Lucas Dailey and Sehyun Oh and Jasmine Stavridi and Gaia Taig and Kathia E. Rodarte and Joseph D. DeAngelo and Andrea Jiang and Brian H. Shim and Jonathan P. Rennhack and John R. Jacob and Melis A. Akinci and Jonathan So and Helen Wang and Federica Piccioni and Jessica A. Talamas and Hans R. Widlund and David E. Root and Clary B. Clish and Nika N. Danial and William C. Hahn},
  journal = {Science Advances},
  year = {2026},
  month = nov,
  doi = {10.1126/sciadv.aej2662},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aej2662},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - MYC primes a paralog synthetic lethality involving the mitochondrial translocase subunits TIMM17A and TIMM17B and N-Acetylaspartate
AU  - Sydney M. Moyer
AU  - Nina Ilic
AU  - Sydney Gang
AU  - Lucas Dailey
AU  - Sehyun Oh
AU  - Jasmine Stavridi
AU  - Gaia Taig
AU  - Kathia E. Rodarte
AU  - Joseph D. DeAngelo
AU  - Andrea Jiang
AU  - Brian H. Shim
AU  - Jonathan P. Rennhack
AU  - John R. Jacob
AU  - Melis A. Akinci
AU  - Jonathan So
AU  - Helen Wang
AU  - Federica Piccioni
AU  - Jessica A. Talamas
AU  - Hans R. Widlund
AU  - David E. Root
AU  - Clary B. Clish
AU  - Nika N. Danial
AU  - William C. Hahn
PY  - 2026
DA  - 2026/11/06
JO  - Science Advances
DO  - 10.1126/sciadv.aej2662
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aej2662
AB  - 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.
SN  - 2375-2548
ER  -