Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Using melanoma as a model, we show here that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a nontranscriptional role in shaping the DDR. On exposure to DNA-damaging agents, MITF is phosphorylated at S325, and its interactome is dramatically remodeled; most transcription cofactors dissociate, and instead MITF interacts with the MRE11–RAD50–NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement with this, high MITF levels are associated with increased single-nucleotide and copy number variant burdens in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of DNA-PKcs-phosphorylated MITF. Our data suggest that a nontranscriptional function of a lineage-restricted transcription factor contributes to a tissue-specialized modulation of the DDR that can impact cancer initiation.

中文翻译：

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DNA 损伤重塑 MITF 相互作用组以增加黑色素瘤基因组的不稳定性

由于基因组不稳定性会驱动癌症的发生和进展，细胞已经进化出高效且普遍存在的 DNA 损伤反应 (DDR) 程序。然而，某些细胞（例如皮肤细胞）通常会暴露于高水平的 DNA 损伤剂。这些高风险细胞是否具有针对组织进行 DNA 修复的谱系特异性机制，目前仍不清楚。使用黑色素瘤作为模型，我们在此表明​​小眼相关转录因子 MITF（一种谱系附加癌基因，协调黑色素细胞和黑色素瘤生物学的许多方面）在塑造 DDR 中发挥非转录作用。当暴露于 DNA 损伤剂时，MITF 在 S325 处被磷酸化，并且其相互作用组被显着重塑；大多数转录辅因子解离，而 MITF 与 MRE11-RAD50-NBS1 (MRN) 复合物相互作用。因此，具有高 MITF 水平的细胞会积累停滞的复制叉，并在同源重组介导的修复中表现出缺陷，这些修复与受损的 MRN 募集到 DNA 损伤相关。与此一致的是，高 MITF 水平与黑色素瘤中单核苷酸和拷贝数变异负担的增加有关。值得注意的是，SUMO 化缺陷型 MITF-E318K 黑色素瘤易感性突变再现了 DNA-PKcs 磷酸化 MITF 的影响。我们的数据表明，谱系限制性转录因子的非转录功能有助于 DDR 的组织特异性调节，从而影响癌症的发生。