Cancer-associated histone mutation H2BG53D disrupts DNA-histone octamer interaction and promotes oncogenic phenotypes

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

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Author(s)

Detail(s)

Original languageEnglish
Article number27
Journal / PublicationSignal Transduction and Targeted Therapy
Volume5
Online published6 Mar 2020
Publication statusPublished - 2020

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Abstract

Histones are nuclear proteins crucial for the packaging of genomic DNA and regulating gene expression. Recent reports including ours have revealed and characterized mutations in genes encoding histone H3 in a variety of diseases; H3K27M in DIPG and H3K36M in chondroblastoma. These histone H3 mutants alter gene expression via changing histone methylations in trans (K-to-M). However, whether additional driver histone mutations exist in other malignancies remain largely unknown. Here we report the identification of a novel H2BG53-to-D missense mutation in Pancreatic Ductal Adenocarcinoma (PDAC). We show that the substitution of the evolutionarily conserved glycine at H2B-53 to aspartic acid weakens the DNA-histone octamer interaction and alters nucleosome stability. We find that the H2BG53D mutation has not effect on DNA replication or DNA damage repair but enhances transcription elongation in vitro. Using CRISPR-Cas9 approach we generated H2BG53D knockin pancreatic cancer cells expressing the G53D-mutant H2B at physiological level mimicking patient conditions. The H2BG53D mutant cells displayed increased cell migration phenotypes, revealing the cancer promoting effect of the H2BG53D mutation in PDAC.

Research Area(s)

  • METHYLATION, REPROGRAMS

Citation Format(s)

Cancer-associated histone mutation H2BG53D disrupts DNA-histone octamer interaction and promotes oncogenic phenotypes. / Wan, Yi Ching Esther; Leung, Tsz Chui Sophia; Ding, Dongbo; Sun, Xulun; Liu, Jiaxian; Zhu, Lina; Kang, Tze Zhen Evangeline; Yang, Du; Zhang, Yuchen; Zhang, Jitian; Qian, Chengmin; Huen, Michael Shing Yan; Li, Qing; Chow, Maggie Zi Ying; Zheng, Zongli; Han, Junhong; Goel, Ajay; Wang, Xin; Ishibashi, Toyotaka; Chan, Kui Ming.

In: Signal Transduction and Targeted Therapy, Vol. 5, 27, 2020.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

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