Loss of the Methyl Lysine Effector Protein PHF20 Impacts the Expression of Genes Regulated by the Lysine Acetyltransferase MOF

Badeaux, Aimee I.; Yang, Yanzhong; Cardenas, Kim; Vemulapalli, Vidyasiri; Chen, Kaifu; Kusewitt, Donna F.; Richie, Ellen R.; Li, Wei; Bedford, Mark T.

doi:10.1074/jbc.m111.271163

Cited by 32 publications

(34 citation statements)

References 21 publications

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“…Recent in vivo and in vitro studies demonstrate that PHF20 transcriptionally regulates p53 in an Akt-dependent manner (Park et al, 2012) and promotes nuclear factor κB (NF-κB) transcriptional activity (Zhang et al, 2013). Loss of PHF20 results in a decreased expression of genes with elevated H4K16ac levels at their promoters, further supporting the notion that PHF20 acts as a transcriptional regulator (Badeaux et al, 2012). …”

Section: Introductionsupporting

confidence: 65%

“…Overexpression of PHF20 is proposed to drive constitutive NF-κB activation in some tumors (Zhang et al, 2013). PHF20 knockout mice die shortly after birth and display a variety of phenotypes within the skeletal and hematopoietic systems (Badeaux et al, 2012). PHF20 deficiency halts conversion of somatic cells into induced pluripotent stem cells (iPSCs), revealing a requirement of this factor for cell reprogramming (Zhao et al, 2013a).…”

Section: Introductionmentioning

confidence: 99%

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PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation

et al. 2016

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SUMMARY PHF20 is a core component of the lysine acetyltransferase complex MOF (male absent on the first)-NSL (non-specific lethal) that generates the major epigenetic mark H4K16ac and is necessary for transcriptional regulation and DNA repair. The role of PHF20 in the complex remains elusive. Here, we report on functional coupling between methylation readers in PHF20. We show that the plant homeodomain (PHD) finger of PHF20 recognizes dimethylated lysine 4 of histone H3 (H3K4me2) and represents an example of a native reader that selects for this modification. Biochemical and structural analyses help to explain this selectivity and the preference of Tudor2, another reader in PHF20, for dimethylated p53. Binding of the PHD finger to H3K4me2 is required for histone acetylation, accumulation of PHF20 at target genes, and transcriptional activation. Together, our findings establish a unique PHF20-mediated link between MOF histone acetyltransferase (HAT), p53, and H3K4me2, and suggest a model for rapid spreading of H4K16ac-enriched open chromatin.

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Section: Introductionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation

et al. 2016

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“…Recent evidence suggests that the key function of histone modifications is to signal for recruitment or activity of effector molecules to DNA [42]. A Tudor domain in PHF20 has been identified, with PHF20 shown to act as a methyllysine binding protein during histone acetyltransferase protein complex formation [43]. These data suggest that PHF20 may be involved in the formation of p53-dependent transcriptional complexes bound to histones in response to DNA damage in cancer cells.…”

Section: Accepted Manuscriptmentioning

confidence: 80%

PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage

Park

et al. 2013

Cellular Signalling

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Publisher rights This is the author's version of a work that was accepted for publication in Cellular Signalling. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Cellular Signalling, VOL25, ISSUE1, 01/2013General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Running Head: Regulation of PHF20 by PKB Keywords : PHF20, Glioblastoma, PKB, p53, protein phosphorylation A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 Abstract PHD finger protein 20 (PHF20) is a transcription factor, which was originally identified in glioma patients. PHF20 appears to be a novel antigen in glioma, and has also termed gliomaexpressed antigen 2. PHF20 is thought to contribute to the development of cancers, including glioblastoma, lung cancer, colon cancer and ovarian cancer. However, little is known about the function of PHF20 in various cancers. Here we report that PHF20 contains two consensus sites for protein kinase B (PKB) phosphorylation (RxRxxS/T). PKB can directly phosphorylate PHF20 on Ser291 in vitro and in vivo. It has been shown that PKB participates in the tumor suppressor p53 regulated gene expression program and has a direct effect on p21 regulation after DNA damage. UV induced DNA damage result in accumulation of p53 and PKB activation. Interestingly, PKB-mediated PHF20 phosphorylation led to an inhibition of p53 induction following UV treatment, leading to the reduction of p21 transcriptional activity.Using anti PHF20 and anti pPKB (S473) antibodies, these events were mapped in various human cancer tissues. Taken together, these data suggest that PHF20 is a novel substrate for PKB and its phosphorylation by PKB plays an important role in tumorigenesis via regulating of p53 mediated signaling.

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“…Supporting the idea that protein dimerization bridges two histone or histone-mimic motifs together, PHF20 forms a homo-dimer that has a greatly enhanced capacity to bind p53 modified on two different lysine residues, simultaneously, as opposed to a single modification 94 . PHF20 works as a co-activator with the histone acetyltransferase MOF 95 , and together they enhance the transcription factor function of p53 96 , suggesting that double modification at the p53 CTD to allow PHF20 binding could greatly enhance p53 activity. One possible explanation for disparate reports of the p53 CTD functions and its importance may be because it is indeed an extensively modified region.…”

Section: Regulation Through Histone Mimicsmentioning

confidence: 99%

Emerging roles for chromatin as a signal integration and storage platform

Badeaux

Shi

2013

Nat Rev Mol Cell Biol

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270

224

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Cells of a multicellular organism, all containing nearly identical genetic information, respond to differentiation cues in variable ways. In addition, cells are plastic, able to execute their specialized function while maintaining the ability to adapt to environmental changes. This is achieved through multiple mechanisms, including the direct regulation of chromatin-based processes in response to stimuli. How signal transduction pathways directly communicate with chromatin to change the epigenetic landscape is poorly understood. The preponderance of covalent modifications on histone tails coupled with a relatively small number of functional outputs raises the possibility that chromatin acts as a site of signal integration and storage.

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Loss of the Methyl Lysine Effector Protein PHF20 Impacts the Expression of Genes Regulated by the Lysine Acetyltransferase MOF

Cited by 32 publications

References 21 publications

PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation

PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation

PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage

Emerging roles for chromatin as a signal integration and storage platform

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