FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells
| Autor: | Shen, J.Z., Qiu, Z., Wu, Q., Finlay, D., Garcia, G., Sun, D., Rantala, J., Barshop, W., Hope, J.L., Gimple, R.C., Sangfelt, O., Bradley, L.M., Wohlschlegel, J., Rich, J.N., Spruck, C. |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA Replication
Adult Male Cell Survival Drug Resistance Methylation SUV39H1 Medical and Health Sciences Repetitive Sequences Cell Line H3K9me3 Histones Double-Stranded Genetic Neoplasms Genetics Humans 2.1 Biological and endogenous factors Aetiology Immune Checkpoint Inhibitors Cell Proliferation Cancer Neoplastic Tumor Nucleic Acid Lysine F-Box Proteins DNA Breaks Immunity FBXO44 Middle Aged Biological Sciences Nucleosomes Neoplasm Proteins repetitive elements Treatment Outcome Infectious Diseases Gene Expression Regulation Neoplasm Female Interferons immunotherapy Transcription Signal Transduction Biotechnology Developmental Biology |
| Zdroj: | Cell, vol 184, iss 2 |
| ISSN: | 0092-8674 |
| Popis: | 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 Tcell 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. |
| Databáze: | OpenAIRE |
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