title: EGFR modulates DNA synthesis and repair through Tyr phosphorylation of histone H4.
abstract: Posttranslational modifications of histones play fundamental roles in many biological functions. Specifically, histone H4-K20 methylation is critical for DNA synthesis and repair. However, little is known about how these functions are regulated by the upstream stimuli. Here, we identify a tyrosine phosphorylation site at Y72 of histone H4, which facilitates recruitment of histone methyltransferases (HMTases), SET8 and SUV4-20H, to enhance its K20 methylation, thereby promoting DNA synthesis and repair. Phosphorylation-defective histone H4 mutant is deficient in K20 methylation, leading to reduced DNA synthesis, delayed cell cycle progression, and decreased DNA repair ability. Disrupting the interaction between epidermal growth factor receptor (EGFR) and histone H4 by Y72 peptide significantly reduced tumor growth. Furthermore, EGFR expression clinically correlates with histone H4-Y72 phosphorylation, H4-K20 monomethylation, and the Ki-67 proliferation marker. These findings uncover a mechanism by which EGFR transduces signal to chromatin to regulate DNA synthesis and repair.
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors: Ruey-Hwang
authors: RH
authors: Chou
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Ying-Nai
authors: YN
authors: Wang
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
authors: Yi-Hsien
authors: YH
authors: Hsieh
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors: Long-Yuan
authors: LY
authors: Li
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Weiya
authors: W
authors: Xia
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors: Wei-Chao
authors: WC
authors: Chang
authors: Graduate Institute of Pharmaceutical Chemical, China Medical University, Taichung 404, Taiwan.
authors: Ling-Chu
authors: LC
authors: Chang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Chien-Chia
authors: CC
authors: Cheng
authors: Graduate Institute of Chinese Medical Science, China Medical University and Institute of Molecular Biology, National Chung Hsing University, Taichung 402, Taiwan.
authors: Chien-Chen
authors: CC
authors: Lai
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jennifer L
authors: JL
authors: Hsu
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
authors: Wei-Jung
authors: WJ
authors: Chang
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
authors: Shu-Ya
authors: SY
authors: Chiang
authors: Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Hong-Jen
authors: HJ
authors: Lee
authors: Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Hsin-Wei
authors: HW
authors: Liao
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
authors: Pei-Huan
authors: PH
authors: Chuang
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
authors: Hui-Yu
authors: HY
authors: Chen
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
authors: Hung-Ling
authors: HL
authors: Wang
authors: Graduate Institute of Pharmaceutical Chemical, China Medical University, Taichung 404, Taiwan.
authors: Sheng-Chu
authors: SC
authors: Kuo
authors: Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors: Chung-Hsuan
authors: CH
authors: Chen
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: ylyu@mail.cmu.edu.tw.
authors: Yung-Luen
authors: YL
authors: Yu
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: mhung@mdanderson.org.
authors: Mien-Chie
authors: MC
authors: Hung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004261:DNA Replication; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059767:Recombinational DNA Repair; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D006657:Histones; D014443:Tyrosine; D066246:ErbB Receptors