Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses
Mutations in histone H3.3-encoding genes causing mutant histone tails are associated with specific cancers such as pediatric glioblastomas (H3.3-G34R/V) and giant cell tumor of the bone (H3.3-G34W). The mechanisms by which these mutations promote malignancy are not completely understood. Here we sho...
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| Hauptverfasser: | , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
14 February 2024
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| In: |
International journal of cancer
Year: 2024, Jahrgang: 154, Heft: 12, Pages: 2106-2120 |
| ISSN: | 1097-0215 |
| DOI: | 10.1002/ijc.34883 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1002/ijc.34883 Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.34883 
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| Verfasserangaben: | Daniela Mancarella, Henrik Ellinghaus, Gianluca Sigismondo, Olivera Veselinov, Alexander Kühn, Ashish Goyal, Mark Hartmann, Jörg Fellenberg, Jeroen Krijgsveld, Christoph Plass, Odilia Popanda, Peter Schmezer, Ali Bakr |
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| 245 | 1 | 0 | |a Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses |c Daniela Mancarella, Henrik Ellinghaus, Gianluca Sigismondo, Olivera Veselinov, Alexander Kühn, Ashish Goyal, Mark Hartmann, Jörg Fellenberg, Jeroen Krijgsveld, Christoph Plass, Odilia Popanda, Peter Schmezer, Ali Bakr |
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| 520 | |a Mutations in histone H3.3-encoding genes causing mutant histone tails are associated with specific cancers such as pediatric glioblastomas (H3.3-G34R/V) and giant cell tumor of the bone (H3.3-G34W). The mechanisms by which these mutations promote malignancy are not completely understood. Here we show that cells expressing H3.3-G34W exhibit DNA double-strand breaks (DSBs) repair defects and increased cellular sensitivity to ionizing radiation (IR). Mechanistically, H3.3-G34W can be deposited to damaged chromatin, but in contrast to wild-type H3.3, does not interact with non-homologous end-joining (NHEJ) key effectors KU70/80 and XRCC4 leading to NHEJ deficiency. Together with defective cell cycle checkpoints reported previously, this DNA repair deficiency in H3.3-G34W cells led to accumulation of micronuclei and cytosolic DNA following IR, which subsequently led to activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, thereby inducing release of immune-stimulatory cytokines. These findings suggest a potential for radiotherapy for tumors expressing H3.3-G34W, which can be further improved by combination with STING agonists to induce immune-mediated therapeutic efficacy. | ||
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