Deposition of onco‐histone <scp>H3</scp>.<scp>3‐G34W</scp> leads to <scp>DNA</scp> repair deficiency and activates <scp>cGAS</scp>/<scp>STING</scp>‐mediated immune responses
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
Abstract
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.