Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.

重复元素 (REs) 占人类基因组的 50%，并且通常在转录上沉默，尽管其机制仍然难以捉摸。通过 RNAi 筛选，我们将 FBXO44 鉴定为癌细胞中 REs 的重要抑制因子。FBXO44 在复制叉处结合 H3K9me3 修饰的核小体，并募集 SUV39H1、CRL4 和 Mi-2/NuRD 以转录沉默 DNA 复制后的 REs。FBXO44/SUV39H1 抑制重新激活 REs，导致 DNA 复制压力和刺激癌细胞中的 MAVS/STING 抗病毒途径和干扰素 (IFN) 信号传导，以促进降低致瘤性、增加免疫原性和增强免疫治疗反应。FBXO44 表达与人类癌症中的复制应激、抗病毒途径、IFN 信号传导和细胞毒性 T 细胞浸润呈负相关，而 FBXO44 免疫基因特征与癌症患者的免疫治疗反应改善相关。FBXO44/SUV39H1 在正常细胞中是可有可无的。总的来说，FBXO44/SUV39H1 是 RE 转录的关键抑制因子，它们的抑制选择性地诱导癌细胞中的 DNA 复制应激和病毒模拟。