Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer
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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2024
|
| _version_ | 1826312107985993728 |
|---|---|
| author | Hosseini, A Lindholm, HT Chen, R Mehdipour, P Marhon, SA Ishak, CA Moore, PC Classon, M Di Gioacchino, A Greenbaum, B De Carvalho, DD |
| author_facet | Hosseini, A Lindholm, HT Chen, R Mehdipour, P Marhon, SA Ishak, CA Moore, PC Classon, M Di Gioacchino, A Greenbaum, B De Carvalho, DD |
| author_sort | Hosseini, A |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T08:22:37Z |
| format | Journal article |
| id | oxford-uuid:0e3ca8b6-205d-475b-87b3-1bb5e123d4d8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:22:37Z |
| publishDate | 2024 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:0e3ca8b6-205d-475b-87b3-1bb5e123d4d82024-02-06T15:16:58ZRetroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0e3ca8b6-205d-475b-87b3-1bb5e123d4d8EnglishSymplectic ElementsCell Press2024Hosseini, ALindholm, HTChen, RMehdipour, PMarhon, SAIshak, CAMoore, PCClasson, MDi Gioacchino, AGreenbaum, BDe Carvalho, DDViral 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. |
| spellingShingle | Hosseini, A Lindholm, HT Chen, R Mehdipour, P Marhon, SA Ishak, CA Moore, PC Classon, M Di Gioacchino, A Greenbaum, B De Carvalho, DD Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer |
| title | Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer |
| title_full | Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer |
| title_fullStr | Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer |
| title_full_unstemmed | Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer |
| title_short | Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer |
| title_sort | retroelement decay by the exonuclease xrn1 is a viral mimicry dependency in cancer |
| work_keys_str_mv | AT hosseinia retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT lindholmht retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT chenr retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT mehdipourp retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT marhonsa retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT ishakca retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT moorepc retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT classonm retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT digioacchinoa retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT greenbaumb retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer AT decarvalhodd retroelementdecaybytheexonucleasexrn1isaviralmimicrydependencyincancer |