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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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Main Authors: Mancarella, Daniela (Author) , Ellinghaus, Henrik (Author) , Sigismondo, Gianluca (Author) , Veselinov, Olivera (Author) , Kühn, Alexander (Author) , Goyal, Ashish (Author) , Hartmann, Mark (Author) , Fellenberg, Jörg (Author) , Krijgsveld, Jeroen (Author) , Plass, Christoph (Author) , Popanda, Odilia (Author) , Schmezer, Peter (Author) , Bakr, Ali (Author)
Format: Article (Journal)
Language:English
Published: 14 February 2024
In: International journal of cancer
Year: 2024, Volume: 154, Issue: 12, Pages: 2106-2120
ISSN:1097-0215
DOI:10.1002/ijc.34883
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 22.07.2024
Physical Description:Online Resource
ISSN:1097-0215
DOI:10.1002/ijc.34883

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