Phosphorylation of H2AX at Ser139 and a New Phosphorylation Site Ser16 by RSK2 Decreases H2AX Ubiquitination and Inhibits Cell Transformation

Zhu, Feng; Zykova, Tatyana A.; Peng, Cong; Zhang, Jishuai; Cho, Yong‐Yeon; Zheng, Duo; Yao, Ke; Ya, Wei; Lau, Andy T. Y.; Bode, Ann M.; Dong, Zigang

doi:10.1158/0008-5472.can-10-2012

Cited by 35 publications

(32 citation statements)

References 47 publications

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“…Deficiency of histone H2AX decreases genomic stability and increases tumor susceptibility of normal cells and tissues, suggesting that it might act as a tumor suppressor [27,28] . Increasing evidence, along with our present results show that the function of H2AX involved in regulation of apoptosis is mediated by its C-terminal phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Imatinib induces H2AX phosphorylation and apoptosis in chronic myelogenous leukemia cells in vitro via caspase-3/Mst1 pathway

Zhang¹,

Cao

et al. 2012

Acta Pharmacol Sin

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Aim: Histone H2AX is a novel tumor suppressor and its phosphorylation at the C terminus (Ser139 and Tyr142) is required for tumor cell apoptosis. The aim of the present study was to elucidate the mechanisms underlying imatinib-induced C-terminal phosphorylation of H2AX in chronic myelogenous leukemia cells in vitro. Methods: BCR-ABL-positive K562 cells were used. Microscopy, Western blotting and flow cytometry were used to study the signaling pathways that regulate imatinib-induced H2AX phosphorylation and the apoptotic mechanisms.

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Section: Discussionmentioning

confidence: 99%

Imatinib induces H2AX phosphorylation and apoptosis in chronic myelogenous leukemia cells in vitro via caspase-3/Mst1 pathway

Zhang¹,

Cao

et al. 2012

Acta Pharmacol Sin

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“…These results suggest that S139P is necessary but not sufficient to dictate both cellular outcomes and that other unique modifications or events that function in conjunction with S139P must occur in a pathway-specific manner. A recent study by Zhu et al investigated the role of H2AX Ser139 in epidermal growth factor (EGF)-mediated transformation of cells (140). They observed that EGF treatment resulted in phosphorylation of Ser139 and Ser16 of H2AX; they also identified ribosomal S6 kinase 2 (RSK2) as the enzyme responsible for these modifications (140).…”

Section: Histone H2amentioning

confidence: 99%

“…A recent study by Zhu et al investigated the role of H2AX Ser139 in epidermal growth factor (EGF)-mediated transformation of cells (140). They observed that EGF treatment resulted in phosphorylation of Ser139 and Ser16 of H2AX; they also identified ribosomal S6 kinase 2 (RSK2) as the enzyme responsible for these modifications (140). Their study revealed that EGF-dependent phosphorylation of Ser139 and Ser16 results in stabilization of H2AX and a decrease in AP1 transactivation.…”

Section: Histone H2amentioning

confidence: 99%

A Peek into the Complex Realm of Histone Phosphorylation

Banerjee

Chakravarti

2011

Molecular and Cellular Biology

170

111

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Although discovered long ago, posttranslational phosphorylation of histones has been in the spotlight only recently. Information is accumulating almost daily on phosphorylation of histones and their roles in cellular physiology and human diseases. An extensive cross talk exists between phosphorylation and other posttranslational modifications, which together regulate various biological processes, including gene transcription, DNA repair, and cell cycle progression. Recent research on histone phosphorylation has demonstrated that nearly all histone types are phosphorylated at specific residues and that these modifications act as a critical intermediate step in chromosome condensation during cell division, transcriptional regulation, and DNA damage repair. As with all young fields, apparently conflicting and sometimes controversial observations about histone phosphorylations and their true functions in different species are found in the literature. Accumulating evidence suggests that instead of functioning strictly as part of a general code, histone phosphorylation probably functions by establishing cross talk with other histone modifications and serving as a platform for recruitment or release of effector proteins, leading to a downstream cascade of events. Here we extensively review published information on the complexities of histone phosphorylation, the roles of proteins recognizing these modifications and the resuting physiological outcome, and, importantly, future challenges and opportunities in this fast-moving field.To fit the enormous length of the eukaryotic genome into the nucleus of a tiny cell requires some very sophisticated packaging. But this packaging must also be highly flexible and malleable so that the genome can be correctly replicated, transcribed, and finally translated. To meet these requirements, DNA is organized in a higher-order nucleoprotein complex known as chromatin. The basic unit of chromatin is the nucleosome, which is essentially DNA wrapped around a core of histone proteins. Each nucleosome is made up of an octamer of core histones (two each of H2A, H2B, H3, and H4), and around this histone core, the DNA is wrapped in two superhelical turns of 147 bp (67). Nucleosomes are spaced at intervals and linked by 20 to 60 bp of linker DNA to form an approximately 10-nm "beads on a string" structure, with H1 linker histones contacting the exit and entry points of the DNA strand that is spooled onto each nucleosome (141). Structurally, histones can be divided into the core domain, which makes up approximately 75% of the protein and is composed of histone fold motifs that physically interact with themselves to form the H2A/2B and H3/4 heterodimers, and the flexible tail domain, which makes up the remaining 25% of the protein.The tail domain is structurally undefined but has been found to be highly conserved. The tail domains are located at the amino termini of the four histones and the carboxyl terminus of H2A and are generally defined by their sensitivity to proteases.Nucleosomes are belie...

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“…A recent study showed that MCPH1, a protein associated with DNA damage response, interacts with di-phosphorylated (S139/Y142ph) H2A.X [103]. Finally, recent data showed that H2A.X S16 can also be phosphorylated, and this modification results in decreased H2A.X ubiquitylation and cell transformation [104].…”

Section: H2ax and Dna Damage Repairmentioning

confidence: 99%

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

2015

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The eukaryotic genome is highly complex and compartmentalized into distinct physical and functional domains. Although the majority of genomic DNA is wrapped around histone proteins in the same manner to form repeating units of nucleosomes, the use of distinct histone variants and the myriad of posttranslational modifications (PTMs) on different histones and amino acid residues create great diversity among these nucleosomes. In this review, we summarize some of the most recent findings in the histone variant and PTM fields and update the readers on our current understanding of various histone-related pathways. Furthermore, we discuss how homotypic or heterotypic deposition of histone variants as well as symmetric or asymmetric histone PTMs within the nucleosome context can further expand the diversity and functionality of chromatin. Altogether, this review highlights the complexity of chromatin composition and organization and their regulatory functions within the eukaryotic genome.

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Phosphorylation of H2AX at Ser139 and a New Phosphorylation Site Ser16 by RSK2 Decreases H2AX Ubiquitination and Inhibits Cell Transformation

Cited by 35 publications

References 47 publications

Imatinib induces H2AX phosphorylation and apoptosis in chronic myelogenous leukemia cells in vitro via caspase-3/Mst1 pathway

Imatinib induces H2AX phosphorylation and apoptosis in chronic myelogenous leukemia cells in vitro via caspase-3/Mst1 pathway

A Peek into the Complex Realm of Histone Phosphorylation

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

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