• Media type: E-Article
  • Title: Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses
  • Contributor: 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]
  • Published: 14 February 2024
  • Published in: International journal of cancer ; 154(2024), 12, Seite 2106-2120
  • Language: English
  • DOI: 10.1002/ijc.34883
  • Identifier:
  • Keywords: cGAS/STING-mediated immune responses ; DNA repair ; H3.3-G34W ; radiation
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access