Strengthened DNA repair pathways in tumor cells contribute to the development of resistance to DNA-damaging agents. Consequently, targeting proteins in these pathways is a promising strategy for tumor chemosensitization. Here, we show that the expression of a subset of Fanconi anemia (FA) genes is attenuated in glioblastoma tumor cells deficient in methylthioadenosine phosphorylase ( MTAP ), a common genetic alteration in a variety of cancers. Subsequent experiments in cell line models of different cancer types illustrate that this reduced transcription of FA genes can be recapitulated by blockage of Protein Arginine Methyltransferase 5 (PRMT5), a promising therapeutically targetable epigenetic regulator whose enzymatic activity is compromised in MTAP-deficient cells. Further analyses provide evidence to support that PRMT5 can function as an epigenetic regulator that contributes to the increased expression of FA genes in cancer cells. Most notably and consistent with the essential roles of FA proteins in resolving DNA damage elicited by interstrand crosslinking (ICL) agents, PRMT5 blockage, as well as MTAP loss, sensitizes tumor cells to ICL agents both in vitro and in xenografts. Collectively, these findings reveal a novel epigenetic mechanism underlying the upregulated expression of FA genes in cancer cells and suggest that therapeutically targeting PRMT5 can have an additional benefit of chemosensitizing tumor cells to ICL agents. Implications: PRMT5 positively regulates the expression of FA genes. Inhibition of PRMT5 attenuates FA-dependent DNA repair pathway and sensitizes tumor cells to ICL agents. This article is featured in Highlights of This Issue, [p. 1971][1] [1]: /lookup/volpage/19/1971?iss=12

中文翻译：

---

范可尼贫血基因的表观遗传调控暗示 PRMT5 阻断作为肿瘤化学增敏的策略

肿瘤细胞中增强的 DNA 修复途径有助于产生对 DNA 损伤剂的抗性。因此，靶向这些途径中的蛋白质是一种有前途的肿瘤化学增敏策略。在这里，我们表明范可尼贫血 (FA) 基因子集的表达在缺乏甲基硫腺苷磷酸化酶 (MTAP) 的胶质母细胞瘤肿瘤细胞中减弱，甲基硫腺苷磷酸化酶 (MTAP) 是多种癌症中常见的遗传改变。随后在不同癌症类型的细胞系模型中进行的实验表明，这种减少的 FA 基因转录可以通过阻断蛋白精氨酸甲基转移酶 5 (PRMT5) 来概括，PRMT5 是一种有前途的治疗靶向表观遗传调节剂，其酶活性在 MTAP 缺陷细胞中受到损害。进一步的分析提供的证据支持 PRMT5 可以作为表观遗传调节剂发挥作用，有助于增加癌细胞中 FA 基因的表达。最值得注意的是，与 FA 蛋白在解决由链间交联 (ICL) 剂引起的 DNA 损伤中的重要作用一致，PRMT5 阻断以及 MTAP 丢失使肿瘤细胞在体外和异种移植物中对 ICL 剂敏感。总的来说，这些发现揭示了一种新的表观遗传机制，该机制是 FA 基因在癌细胞中上调表达的基础，并表明治疗性靶向 PRMT5 可以使肿瘤细胞对 ICL 药物化学敏感。意义：PRMT5 正调控 FA 基因的表达。抑制 PRMT5 可减弱 FA 依赖性 DNA 修复途径并使肿瘤细胞对 ICL 药物敏感。这篇文章刊登在本期要闻中，[p。1971][1] [1]: /lookup/volpage/19/1971?iss=12