Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer

Amir Hosseini, Håvard T. Lindholm, Raymond Chen, Parinaz Mehdipour, Sajid A. Marhon, Charles A. Ishak, Paul C. Moore, Marie Classon, Andrea Di Gioacchino, Benjamin Greenbaum, Daniel D. De Carvalho

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Viral mimicry describes the immune response induced by endogenous stimuli such as double-stranded RNA (dsRNA) from endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune responses. Here, we systematically identify mechanisms of viral mimicry adaptation associated with cancer cell dependencies. Among the top hits is the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1 dependency is mediated by mitochondrial antiviral signaling protein and protein kinase R activation and is associated with higher levels of cytosolic dsRNA, higher levels of a subset of Alus capable of forming dsRNA, and higher interferon-stimulated gene expression, indicating that cells die due to induction of viral mimicry. Furthermore, dsRNA-inducing drugs such as 5-aza-2′-deoxycytidine and palbociclib can generate a synthetic dependency on XRN1 in cells initially resistant to XRN1 knockout. These results indicate that XRN1 is a promising target for future cancer therapeutics.

Original languageEnglish
Article number113684
JournalCell Reports
Volume43
Issue number2
DOIs
StatePublished - 27 Feb 2024
Externally publishedYes

Keywords

  • CP: Cancer
  • CP: Immunology
  • XRN1
  • endogenous retroelements
  • viral mimicry

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