EGFR Modulates DNA Synthesis and Repair through Tyr Phosphorylation of Histone H4

Abstract

Summary Posttranslational modifications of histones play fundamental roles in many biological functions. Specifically, histone H4-K20 methylation is critical in 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 mono-methylation, and the Ki-67 proliferation marker. These findings uncover a mechanism by which EGFR transduces signal to chromatin to regulate DNA synthesis and repair.

Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression

“…Elevated levels of STAT1 positively regulate ISG expression independent of pY-STAT1 (Cheon and Stark, 2009). Furthermore, translocation of signaling receptors to the nucleus can positively regulate gene expression as shown for the insulin-like growth factor 1 receptor (Sehat et al, 2010), or the epidermal growth factor receptor that promotes epigenetic modifications (Chou et al, 2014). Thus, both IFNAR1 nuclear localization (Subramaniam and Johnson, 2004) and high STAT1 expression could contribute to ISG expression following IFN-I stimulation, despite the low activation of pY-STAT1.…”

Quantitative Proteomic Analysis of Histone Modifications

“…Recently, identification of tyrosine phosphorylation at H4Y72 offers such an example. 189 In addition, for newly discovered lysine acylation marks, only one or a few cellular systems have been analyzed. Accordingly, additional histone sites bearing these types of modification should exist in other cells.…”

Role for Tyrosine Phosphorylation of A-kinase Anchoring Protein 8 (AKAP8) in Its Dissociation from Chromatin and the Nuclear Matrix

“…In addition, the association of AKAP8 with nuclear structures is involved in gene expression, DNA replication, and mitotic progression (26,56,57). Recently, the nuclear proteins KAT5, histone H4, and HDAC2 were reported to be tyrosinephosphorylated and to functionally associate with chromatin structures (22,54,58). Taken together, we assume that tyrosine phosphorylation of various nuclear proteins, including AKAP8, is attributable to nuclear tyrosine kinase-mediated chromatin structural changes, which could be involved in a variety of nuclear function, such as gene expression, DNA replication, and mitotic progression.…”