Histone H3K27 methylation modulates the dynamics of FANCD2 on chromatin to facilitate NHEJ and genome stability
Abstract
Dysregulation of the homeostatic balance of histone H3 di- and tri-methyl lysine 27 (H3K27me2/3) levels caused by the mis-sense mutation of histone H3 (H3K27M) is reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in patients with diffuse intrinsic pontine glioma (DIPG), dramatically attenuated the presence of 53BP1 (also known as TP53BP1) foci and the capability of non-homologous end joining (NHEJ) in human dermal fibroblasts. H3.1K27M mutant cells showed increased rates of genomic insertions/deletions and copy number variations, as well as an increase in p53-dependent apoptosis. We further showed that both hypo-H3K27me2/3 and H3.1K27M interacted with FANCD2, a central player in the choice of DNA repair pathway. H3.1K27M triggered the accumulation of FANCD2 on chromatin, suggesting an interaction between H3.1K27M and FANCD2. Interestingly, knockdown of FANCD2 in H3.1K27M cells recovered the number of 53BP1-positive foci, NHEJ efficiency and apoptosis rate. Although these findings in HDF cells may differ from the endogenous regulation of the H3.1K27M mutant in the specific tumor context of DIPG, our results suggest a new model by which H3K27me2/3 facilitates NHEJ and the maintenance of genome stability. This article has an associated First Person interview with the first author of the paper.
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Loss of the trimethylation status of H3K27Me3 has been reported to induce senescence through the up-regulation of SASP and p16 pathways, and its loss/decrease is considered a marker of senescent cells.
“Loss of the trimethylation status of H3K27Me3 has been reported to induce senescence through the up-regulation of SASP and p16 pathways, and its loss/decrease is therefore considered a marker of senescent cells [64, 66, 170].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [170]
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References 94 · Cited by 45
- Authors
- Zhang, Y., Chang, J.-F., Sun, J., Chen, L., Yang, X.-M., Tang, H.-Y., Jing, Y.-Y., Kang, X., He, Z.-M., Wu, J.-Y., Wei, H.-M., Wang, D.-L., Xu, R.-G., Zhu, R.-B., Shen, Y., Zeng, S.-Y., Wang, C., Liu, K.-N., Zhang, Y., Mao, Z.-Y., Jiang, C.-Z., & Sun, F.-L.
- Affiliations
- Tongji University (CN)
- Research Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Advanced Institute of Translational Medicine, Tongji University 2 , Shanghai 200092, PR China
- School of Medicine, Tsinghua University 1 , Beijing 100084, PR China
- Tsinghua University (CN)
- ORCID
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2018-06-15
- Volume
- 131
- Issue
- 12
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2802295660
- Cited by
- 45
- References
- 94
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 12 · 2023: 2 · 2022: 2 · 2021: 11 · 2020: 6 · 2019: 6 · 2018: 1
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Natural Science Foundation of China (31330043)
- Ministry of Science and Technology of the People's Republic of China (2017YFA0103301, 2015CB856204, 2015CB964802, 2014CB964603)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- H3K27 methylation, H3K27M mutation, FANCD2, non-homologous end joining, genome stability, 53BP1 foci, DNA repair pathway choice, copy number variation, indels, p53-dependent apoptosis, diffuse intrinsic pontine glioma, histone variants
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, Cell Line, Chromatin, DNA Repair, DNA-Binding Proteins, Fibroblasts, Glioma, Histones, Humans, Methylation, Brain Stem Neoplasms, Genomic Instability, DNA Repair Enzymes, Fanconi Anemia Complementation Group D2 Protein, HEK293 Cells, DNA End-Joining Repair
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