Proteomic profiling and genome-wide mapping of O-GlcNAc chromatin-associated proteins reveal an O-GlcNAc-regulated genotoxic stress response

Yubo Liu, Qiushi Chen, Nana Zhang, Keren Zhang, Tongyi Dou, Yu Cao, Yimin Liu, Kun Li, Xinya Hao, Xueqin Xie, Wenli Li, Yan Ren () and Jianing Zhang ()
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Yubo Liu: Dalian University of Technology
Qiushi Chen: Clinical Laboratory of BGI Health, BGI-Shenzhen
Nana Zhang: Dalian University of Technology
Keren Zhang: Clinical Laboratory of BGI Health, BGI-Shenzhen
Tongyi Dou: Dalian University of Technology
Yu Cao: Dalian University of Technology
Yimin Liu: Dalian University of Technology
Kun Li: Dalian University of Technology
Xinya Hao: Dalian University of Technology
Xueqin Xie: Dalian University of Technology
Wenli Li: Dalian University of Technology
Yan Ren: Clinical Laboratory of BGI Health, BGI-Shenzhen
Jianing Zhang: Dalian University of Technology

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract O-GlcNAc modification plays critical roles in regulating the stress response program and cellular homeostasis. However, systematic and multi-omics studies on the O-GlcNAc regulated mechanism have been limited. Here, comprehensive data are obtained by a chemical reporter-based method to survey O-GlcNAc function in human breast cancer cells stimulated with the genotoxic agent adriamycin. We identify 875 genotoxic stress-induced O-GlcNAc chromatin-associated proteins (OCPs), including 88 O-GlcNAc chromatin-associated transcription factors and cofactors (OCTFs), subsequently map their genomic loci, and construct a comprehensive transcriptional reprogramming network. Notably, genotoxicity-induced O-GlcNAc enhances the genome-wide interactions of OCPs with chromatin. The dynamic binding switch of hundreds of OCPs from enhancers to promoters is identified as a crucial feature in the specific transcriptional activation of genes involved in the adaptation of cancer cells to genotoxic stress. The OCTF nuclear respiratory factor 1 (NRF1) is found to be a key response regulator in O-GlcNAc-modulated cellular homeostasis. These results provide a valuable clue suggesting that OCPs act as stress sensors by regulating the expression of various genes to protect cancer cells from genotoxic stress.

Date: 2020
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DOI: 10.1038/s41467-020-19579-y

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