FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells

Cell. 2021 Jan 21;184(2):352-369.e23. doi: 10.1016/j.cell.2020.11.042. Epub 2020 Dec 23.


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.

Keywords: FBXO44; H3K9me3; SUV39H1; immunotherapy; repetitive elements.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • DNA Breaks, Double-Stranded
  • DNA Replication / genetics*
  • Drug Resistance, Neoplasm
  • F-Box Proteins / metabolism*
  • 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 / genetics*
  • Neoplasms / immunology
  • Nucleosomes / metabolism
  • Repetitive Sequences, Nucleic Acid / genetics*
  • Signal Transduction
  • Transcription, Genetic
  • Treatment Outcome


  • F-Box Proteins
  • FBXO44 protein, human
  • Histones
  • Immune Checkpoint Inhibitors
  • Neoplasm Proteins
  • Nucleosomes
  • Interferons
  • Lysine