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A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis

Author

Listed:
  • Yanzhe Gao

    (University of North Carolina at Chapel Hill)

  • Elizabeth Mutter-Rottmayer

    (University of North Carolina at Chapel Hill
    Curriculum in Toxicology, University of North Carolina at Chapel Hill)

  • Alicia M. Greenwalt

    (University of North Carolina at Chapel Hill
    Curriculum in Genetics and Molecular Biology, University of North Carolina)

  • Dennis Goldfarb

    (University of North Carolina at Chapel Hill)

  • Feng Yan

    (Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill)

  • Yang Yang

    (University of North Carolina at Chapel Hill)

  • Raquel C. Martinez-Chacin

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Kenneth H. Pearce

    (Center For Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill)

  • Satoshi Tateishi

    (Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University)

  • Michael B. Major

    (University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill)

  • Cyrus Vaziri

    (University of North Carolina at Chapel Hill
    Curriculum in Toxicology, University of North Carolina at Chapel Hill
    Curriculum in Genetics and Molecular Biology, University of North Carolina)

Abstract

Trans-lesion synthesis (TLS) is an important DNA-damage tolerance mechanism that permits ongoing DNA synthesis in cells harbouring damaged genomes. The E3 ubiquitin ligase RAD18 activates TLS by promoting recruitment of Y-family DNA polymerases to sites of DNA-damage-induced replication fork stalling. Here we identify the cancer/testes antigen melanoma antigen-A4 (MAGE-A4) as a tumour cell-specific RAD18-binding partner and an activator of TLS. MAGE-A4 depletion from MAGE-A4-expressing cancer cells destabilizes RAD18. Conversely, ectopic expression of MAGE-A4 (in cell lines lacking endogenous MAGE-A4) promotes RAD18 stability. DNA-damage-induced mono-ubiquitination of the RAD18 substrate PCNA is attenuated by MAGE-A4 silencing. MAGE-A4-depleted cells fail to resume DNA synthesis normally following ultraviolet irradiation and accumulate γH2AX, thereby recapitulating major hallmarks of TLS deficiency. Taken together, these results demonstrate a mechanism by which reprogramming of ubiquitin signalling in cancer cells can influence DNA damage tolerance and probably contribute to an altered genomic landscape.

Suggested Citation

  • Yanzhe Gao & Elizabeth Mutter-Rottmayer & Alicia M. Greenwalt & Dennis Goldfarb & Feng Yan & Yang Yang & Raquel C. Martinez-Chacin & Kenneth H. Pearce & Satoshi Tateishi & Michael B. Major & Cyrus Vaz, 2016. "A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12105
    DOI: 10.1038/ncomms12105
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