The DNA damage response (DDR) pathway is a promising target for anticancer therapies. The androgen receptor and myeloblastosis transcription factors have been reported to regulate expression of an overlapping set of DDR genes in prostate cancer cells. Here, we found that histone demethylase JMJD1A regulates expression of a different set of DDR genes largely through c-Myc. Inhibition of JMJD1A delayed the resolution of γ-H2AX foci, reduced the formation of foci containing ubiquitin, 53BP1, BRCA1 or Rad51, and inhibited the reporter activity of double-strand break (DSB) repair. Mechanistically, JMJD1A regulated expression of DDR genes by increasing not only the level but also the chromatin recruitment of c-Myc through H3K9 demethylation. Further, we found that ubiquitin ligase HUWE1 induced the K27-/K29-linked noncanonical ubiquitination of JMJD1A at lysine-918. Ablation of the JMJD1A noncanonical ubiquitination lowered DDR gene expression, impaired DSB repair, and sensitized response of prostate cells to irradiation, topoisomerase inhibitors or PARP inhibitors. Thus, development of agents that target JMJD1A or its noncanonical ubiquitination may sensitize the response of prostate cancer to radiotherapy and possibly also genotoxic therapy.

DNA损伤反应（DDR）途径是抗癌治疗的有希望的目标。据报道，雄激素受体和成纤维细胞病的转录因子可调节前列腺癌细胞中一组重叠的DDR基因的表达。在这里，我们发现组蛋白脱甲基酶JMJD1A主要通过c-Myc调节另一组DDR基因的表达。抑制JMJD1A延迟了γ-H2AX灶的分离，减少了含有泛素，53BP1，BRCA1或Rad51的灶的形成，并抑制了双链断裂（DSB）修复的报告基因活性。从机理上讲，JMJD1A通过通过H3K9去甲基化不仅增加c-Myc的水平，而且增加染色质的募集，从而调节DDR基因的表达。进一步，我们发现泛素连接酶HUWE1在赖氨酸918诱导JMJD1A的K27- / K29连锁非规范泛素化。JMJD1A非规范泛素化的消融降低了DDR基因的表达，损害了DSB的修复，并使前列腺细胞对放射线，拓扑异构酶抑制剂或PARP抑制剂的敏感性增强。因此，靶向JMJD1A或其非规范泛素化的药物的开发可能会使前列腺癌对放射疗法和可能的遗传毒性疗法的反应更加敏感。