Benzo(a)pyrene (BaP) or benzo (a) pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE) exposure causes trophoblast cell dysfunctions and induces miscarriage, which is generally epigenetically regulated. Homologous recombination (HR) repair of DNA double strand break (DSB) plays a crucial role in maintenance of genetic stability and cell normal functions. However, whether BaP/BPDE might suppress HR repair in human trophoblast cells to induce miscarriage, as well as its epigenetic regulatory mechanism, is largely unclear. In this study, we find that BaP/BPDE suppresses HR repair of DSB in trophoblast cells and eventually induces miscarriage by up-regulating lnc-HZ08. In mechanism, lnc-HZ08 (1) down-regulates the expression levels of FOXA1 (forkhead box A1) and thus suppresses FOXA1-mediated mRNA transcription of BRCA1 (Breast cancer susceptibility gene 1) and CtIP (CtBP-interacting protein), (2) impairs BRCA1 and CtIP protein interactions by competitive binding with CtIP through lnc-HZ08-1 fragment, and also (3) suppresses BRCA1-mediated CtIP ubiquitination without affecting CtIP stability, three of which eventually suppress HR repair in human trophoblast cells. Supplement with murine Ctip could efficiently restore (i.e. increase) HR repair and alleviate miscarriage in BaP-exposed mouse model. Collectively, this study not only reveals the association and causality among BaP/BPDE exposure, the defective HR repair, and miscarriage, but also discovers novel mechanism in lnc-HZ08-regulated BRCA1/CtIP-mediated HR repair, bridging epigenetic regulation and genetic instability and also providing an efficient approach for treatment against BaP/BPDE-induced unexplained miscarriage.

中文翻译：

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BaP/BPDE 抑制人滋养层细胞同源重组修复诱导流产：lnc-HZ08 的作用


苯并(a)芘 (BaP) 或苯并 (a) 芘 7,8-二氢二醇-9,10-环氧化物 (BPDE) 暴露会导致滋养层细胞功能障碍并诱导流产，这通常是表观遗传调控的。 DNA双链断裂(DSB)的同源重组(HR)修复在维持遗传稳定性和细胞正常功能中发挥着至关重要的作用。然而，BaP/BPDE是否可能抑制人滋养层细胞的HR修复从而诱导流产，及其表观遗传调控机制目前尚不清楚。在这项研究中，我们发现 BaP/BPDE 抑制滋养层细胞中 DSB 的 HR 修复，并最终通过上调 lnc-HZ08 诱导流产。在机制上，lnc-HZ08 (1) 下调 FOXA1（叉头盒 A1）的表达水平，从而抑制 FOXA1 介导的 BRCA1（乳腺癌易感基因 1）和 CtIP（CtBP 相互作用蛋白）的 mRNA 转录，(2 ) 通过 lnc-HZ08-1 片段与 CtIP 竞争性结合，从而损害 BRCA1 和 CtIP 蛋白相互作用，并且 (3) 抑制 BRCA1 介导的 CtIP 泛素化而不影响 CtIP 稳定性，其中三个最终抑制人滋养层细胞中的 HR 修复。补充小鼠 Ctip 可以有效恢复（即增加）HR 修复并减轻 BaP 暴露小鼠模型的流产。总的来说，这项研究不仅揭示了 BaP/BPDE 暴露、HR 修复缺陷和流产之间的关联和因果关系，而且还发现了 lnc-HZ08 调节的 BRCA1/CtIP 介导的 HR 修复、桥接表观遗传调控和遗传不稳定性的新机制。还为治疗 BaP/BPDE 引起的不明原因流产提供了有效的方法。