BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma
BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma
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DOI：
10.1101/gad.314633.118
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发表时间：
2019-03-01
影响因子：
10.5
通讯作者：
Goding, Colin R.
中科院分区：
文献类型：
--
作者：
Herbert, Katharine;Binet, Romuald;Goding, Colin R.
暴露于高水平的环境损伤的细胞类型是否具有细胞类型特异性的专业生存机制或增强的DNA损伤修复能力。 BRN2是与神经发育和几种癌症有关的组织限制的POU结构域转录因子。在黑色素瘤中，BRN2在促进入侵和调节增殖方面起着关键作用。在这里，我们发现BRN2与DNA损伤响应蛋白相关，而不是与转录辅因子相互作用，而是直接结合PARP1和KU70/KU80。与DNA损伤部位的快速pARP1依赖性BRN2的关联有助于KU80的募集，并通过促进KU依赖性的非同源终端加入（NHEJ）来募集DNA损伤修复，而同源重组为代价。 BRN2还抑制了与凋亡相关的基因表达程序，以防止UVB-化学疗法和vemurafenib诱导的细胞凋亡。值得注意的是，BRN2表达也与人类黑色素瘤中的高单核苷酸变异率相关。通过通过NHEJ促进容易发生的DNA损伤修复并抑制受损细胞的凋亡，我们的结果表明，BRN2有助于产生具有高突变负担的黑色素瘤。我们的发现突出了关键转录因子在重编程DNA损伤修复中的新作用，并表明BRN2可能会影响表达BRN2表达癌症中对DNA损害剂的反应。
Whether cell types exposed to a high level of environmental insults possess cell type-specific prosurvival mechanisms or enhanced DNA damage repair capacity is not well understood. BRN2 is a tissue-restricted POU domain transcription factor implicated in neural development and several cancers. In melanoma, BRN2 plays a key role in promoting invasion and regulating proliferation. Here we found, surprisingly, that rather than interacting with transcription cofactors, BRN2 is instead associated with DNA damage response proteins and directly binds PARP1 and Ku70/Ku80. Rapid PARP1-dependent BRN2 association with sites of DNA damage facilitates recruitment of Ku80 and reprograms DNA damage repair by promoting Ku-dependent nonhomologous end-joining (NHEJ) at the expense of homologous recombination. BRN2 also suppresses an apoptosis-associated gene expression program to protect against UVB-, chemotherapy- and vemurafenib-induced apoptosis. Remarkably, BRN2 expression also correlates with a high single-nucleotide variation prevalence in human melanomas. By promoting error-prone DNA damage repair via NHEJ and suppressing apoptosis of damaged cells, our results suggest that BRN2 contributes to the generation of melanomas with a high mutation burden. Our findings highlight a novel role for a key transcription factor in reprogramming DNA damage repair and suggest that BRN2 may impact the response to DNA-damaging agents in BRN2-expressing cancers.