Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism
Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism
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DOI：
10.1016/j.ajhg.2021.04.021
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发表时间：
2021-06-03
影响因子：
9.8
通讯作者：
Nomura, Toshifumi
中科院分区：
文献类型：
--
作者：
Miyauchi, Toshinari;Suzuki, Shotaro;Nomura, Toshifumi
回复突变嵌合现象，或“自然基因疗法”，是指体细胞中遗传突变的体内自发回复。只有大约50种人类遗传性疾病表现出回复突变嵌合现象，暗示突变蛋白在致病性生殖系突变的体细胞校正中发挥了独特的作用。然而，在这些疾病中突变蛋白诱导体细胞遗传逆转的过程仍然未知。在这里，我们表明，杂合致病性CARD 14突变引起自身炎症性皮肤病，包括银屑病和毛发红色糠疹，主要是通过同源重组修复。突变CARD 14在复制应激条件下增加了DNA双链断裂，而不是改变DNA对外源刺激（如X射线照射或依托泊苷处理）的损伤反应。此外，突变CARD 14抑制了新的起点发射，而不促进复制应激状态下的交叉事件。总之，这些结果表明，突变CARD 14改变复制应激反应，并优先驱动断裂诱导的复制（BIR），这通常是抑制在真核生物。我们的研究结果突出了BIR参与逆转事件，从而揭示了BIR以前未描述的作用，可能被利用来开发目前难治性遗传疾病的治疗方法。
Revertant mosaicism, or "natural gene therapy,'' refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.