Back to Search
Start Over
FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells.
- Source :
-
Cell [Cell] 2021 Jan 21; Vol. 184 (2), pp. 352-369.e23. Date of Electronic Publication: 2020 Dec 23. - Publication Year :
- 2021
-
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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Cell Line, Tumor
Cell Proliferation genetics
Cell Survival genetics
DNA Breaks, Double-Stranded
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
Histones metabolism
Humans
Immune Checkpoint Inhibitors pharmacology
Immune Checkpoint Inhibitors therapeutic use
Immunity
Interferons metabolism
Lysine metabolism
Male
Methylation
Middle Aged
Neoplasm Proteins metabolism
Neoplasms immunology
Nucleosomes metabolism
Signal Transduction
Transcription, Genetic
Treatment Outcome
DNA Replication genetics
F-Box Proteins metabolism
Neoplasms genetics
Repetitive Sequences, Nucleic Acid genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 184
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 33357448
- Full Text :
- https://doi.org/10.1016/j.cell.2020.11.042