Histone H3K27 methylation modulates the dynamics of FANCD2 on chromatin to facilitate NHEJ and genome stability

Journal of Cell Science
Ye ZhangFang-Lin Sun

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 n...Continue Reading

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Citations

Jun 6, 2019·Critical Reviews in Biochemistry and Molecular Biology·Jae Jin KimKyle M Miller
Nov 16, 2019·Acta Neuropathologica Communications·Nicole SchwabLili-Naz Hazrati
May 16, 2019·Molecular and Cellular Biology·Karissa L PaquinNiall G Howlett
Oct 4, 2020·Cancers·Henriette PedersenPetra Hamerlik
Nov 11, 2020·Cells·Juliette FerrandSophie E Polo
Nov 5, 2019·Molecular Cancer Research : MCR·Tshering D Lama-Sherpa, Lalita A Shevde
May 10, 2021·Bioorganic Chemistry·Xiuhong WeiFengyuan Che
Jun 5, 2021·Mutation Research. Reviews in Mutation Research·Yuchuan Zhou, Chunlin Shao
Aug 22, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ivan Menendez-MontesHesham A Sadek

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