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.

• Authors: Ye Zhang, Jian-Feng Chang, Jin Sun, Lu Chen, Xiao-Mei Yang, Huan-Yin Tang, Yuan-Ya Jing, Xuan Kang, Zhi-Min He, Jun-Yu Wu, Hui-Min Wei, Da-Liang Wang, Rong-Gang Xu, Rui-Bao Zhu, Ying Shen, Shi-Yang Zeng, Chen Wang, Kui-Nan Liu, Yong Zhang, Zhi-Yong Mao, Ci-Zhong Jiang, Fang-Lin Sun
• Journal: Journal of cell science (J Cell Sci) Vol. 131 Issue 12 (06 21 2018) ISSN: 1477-9137 [Electronic] England
• PMID: 29760279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018. Published by The Company of Biologists Ltd.

Chemical References

• Chromatin
• DNA-Binding Proteins
• FANCD2 protein, human
• Fanconi Anemia Complementation Group D2 Protein
• Histones
• NHEJ1 protein, human
• TP53BP1 protein, human
• Tumor Suppressor p53-Binding Protein 1
• DNA Repair Enzymes

Topics

• Brain Stem Neoplasms (genetics, metabolism)
• Cell Line
• Chromatin (genetics, metabolism)
• DNA End-Joining Repair
• DNA Repair
• DNA Repair Enzymes (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Fanconi Anemia Complementation Group D2 Protein (genetics, metabolism)
• Fibroblasts
• Genomic Instability
• Glioma (genetics, metabolism)
• HEK293 Cells
• Histones (genetics, metabolism)
• Humans
• Methylation
• Tumor Suppressor p53-Binding Protein 1 (genetics, metabolism)