A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis.
A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis.
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DOI：
10.1038/ncomms12105
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发表时间：
2016-07-05
影响因子：
16.6
通讯作者：
Vaziri C
中科院分区：
文献类型：
--
作者：
Gao Y;Mutter-Rottmayer E;Greenwalt AM;Goldfarb D;Yan F;Yang Y;Martinez-Chacin RC;Pearce KH;Tateishi S;Major MB;Vaziri C
跨损伤合成(TLS)是一种重要的DNA损伤耐受机制，允许含有受损基因组的细胞进行DNA合成。E3泛素连接酶RAD18通过促进Y-家族DNA聚合酶在DNA损伤诱导的复制分叉停滞位点的募集来激活TLS。在这里，我们确定了肿瘤/睾丸抗原黑色素瘤抗原-A4(MAGE-A4)是肿瘤细胞特异性的RAD18结合伙伴和TLS的激活剂。表达MAGE-A4的癌细胞的MAGE-A4缺失会破坏RAD18的稳定性。相反，MAGE-A4的异位表达(在缺乏内源性MAGE-A4的细胞系中)促进RAD18的稳定性。DNA损伤诱导的RAD18底物增殖细胞核抗原的单一泛素化可通过MAGE-A4沉默而减弱。MAGE-A4缺失的细胞在紫外线照射后不能恢复正常的DNA合成，并积累TLSH2AX，从而概括了γ缺乏的主要特征。综上所述，这些结果证明了一种机制，通过这种机制，癌细胞中泛素信号的重新编程可以影响DNA损伤耐受性，并可能导致基因组格局的改变。RAD18是跨损伤合成的重要蛋白质，是一种容易出错的DNA复制损伤容忍模式。在这里，作者展示了MAGE-A4稳定RAD18，并允许癌细胞在面对遗传毒性损伤时保持正在进行的DNA合成。
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. RAD18 is an important protein in trans-lesion synthesis, an error-prone damage-tolerant mode of DNA replication. Here the authors show that MAGE-A4 stabilizes RAD18 and allows cancer cells to maintain on-going DNA synthesis in the face of genotoxic injury.