PXD047223

PXD047223 is an original dataset announced via ProteomeXchange.

Title	Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses
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. 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. As a consequence H3.3-G34W cells displayed an accumulation of micronuclei and cytosolic DNA, which led to activation of the cyclic GMP–AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, thereby inducing release of immunestimulatory 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.
HostingRepository	PRIDE
AnnounceDate	2025-04-08
AnnouncementXML	Submission_2025-04-08_03:38:30.955.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gianluca Sigismondo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-24 07:45:20	ID requested
⏵ 1	2025-04-08 03:38:31	announced

10.1002/ijc.34883;

Mancarella D, Ellinghaus H, Sigismondo G, Veselinov O, K, ü, hn A, Goyal A, Hartmann M, Fellenberg J, Krijgsveld J, Plass C, Popanda O, Schmezer P, Bakr A, Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses. Int J Cancer, 154(12):2106-2120(2024) [pubmed]

submitter keyword: H3.3, onco-histone, DNA repair, immune response, G34W, cGAS/STING

Ali Bakr
contact affiliation	German Cancer Research Center, Division of Cancer Epigenomics
contact email	a.bakr@dkfz-heidelberg.de
lab head
Gianluca Sigismondo
contact affiliation	DKFZ
contact email	gianluca.sigismondo@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047223
     1. Label: PRIDE project
     2. Name: Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses