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

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 Vaziri

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish
Article number12105
JournalNature communications
Volume7
DOIs
StatePublished - Jul 5 2016

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