Journal article
FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells
21 Jan 2021
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells
- Creators
- J.Z Shen - Discovery InstituteZ Qiu - Sanford Consortium for Regenerative MedicineQ Wu - Sanford Consortium for Regenerative MedicineD Finlay - Discovery InstituteG Garcia - Discovery InstituteD Sun - Discovery InstituteJ Rantala - University of SheffieldW Barshop - University of California, Los AngelesJ.L Hope - Discovery InstituteR.C Gimple - Sanford Consortium for Regenerative MedicineO Sangfelt - Karolinska InstitutetL.M Bradley - Discovery InstituteJ Wohlschlegel - University of California, Los AngelesJ.N Rich - Sanford Consortium for Regenerative MedicineC Spruck - Discovery Institute
- Publisher
- Elsevier BV
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000612290800011
- Scopus ID
- 2-s2.0-85099129270
- Other Identifier
- 991021448188204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology