O-linked
            <i>N</i>
            -acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence

Lee, Jong Sun; Zhang, Zhiguo

doi:10.1073/pnas.1600509113

Cited by 31 publications

(30 citation statements)

References 77 publications

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“…For example, reconstituted synthetic histone nucleosomes show destabilized H2A–H2B dimers, which mimic an open chromatin state [35]. Furthermore, the histone chaperone complex FACT (Facilitates chromatin transcripts) interacts with synthetic nucleosomes containing a synthetic O -GlcNAc site at H2A-S112 [36], while OGT is known to interact with the histone chaperone HIRA complex promoting nucleosome assembly of H3.3 [37]. These data suggest a role for O-GlcNAcylation in modulating the composition and structure of the nucleosome and hint at an important role for S-phase histone O-GlcNAcylation.…”

Section: O-glcnac Cycling In Interphasementioning

confidence: 99%

The sweet side of the cell cycle

Tan

Duncan

Slawson

2017

Biochemical Society Transactions

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Cell division (mitosis) and gamete production (meiosis) are fundamental requirements for normal organismal development. The mammalian cell cycle is tightly regulated by different checkpoints ensuring complete and precise chromosomal segregation and duplication. In recent years, researchers have become increasingly interested in understanding how O-GlcNAc regulates the cell cycle. The O-GlcNAc post-translation modification is an O-glycosidic bond of a single β-N-acetylglucosamine sugar to serine/threonine residues of intracellular proteins. This modification is sensitive toward changes in nutrient levels in the cellular environment making O-GlcNAc a nutrient sensor capable of influencing cell growth and proliferation. Numerous studies have established that O-GlcNAcylation is essential in regulating mitosis and meiosis, while loss of O-GlcNAcylation is lethal in growing cells. Moreover, aberrant O-GlcNAcylation is linked with cancer and chromosomal segregation errors. In this review, we will discuss how O-GlcNAc controls different aspects of the cell cycle with a particular emphasis on mitosis and meiosis.

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Section: O-glcnac Cycling In Interphasementioning

confidence: 99%

The sweet side of the cell cycle

Tan

Duncan

Slawson

2017

Biochemical Society Transactions

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“…This result suggests that the TPR domain alone can select OGT substrate proteins without the presence of the catalytic domain. In addition, 8 (indicated by an italicized and bold protein name in Table 1) of the identified proteins had previously been demonstrated to specifically interact with OGT, where "interaction" here is defined as a one or two directional co-immunoprecipitation [14][15][16][34][35][36][37] . Together, these factors lend confidence to the novel protein IDs in the dataset.…”

Section: Defining the Ogt Tpr Interactome In Hela Cellsmentioning

confidence: 99%

Generation of an Unbiased Interactome for the Tetratricopeptide Repeat Domain of O-GlcNAc Transferase Indicates a Role for the Enzyme in Intellectual Disability

Stephen

Praissman

Wells

2020

Preprint

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The O-GlcNActransferase (OGT) is localized to the nucleus and cytoplasm where it regulates nucleocytoplasmic proteins by modifying serine and threonine residues with a non-extended monosaccharide, b-N-Acetyl-Glucosamine (O-GlcNAc). With thousands ofknown O-GlcNAcmodifiedproteinsbut only oneOGTencoded in the mammalian genome, a prevailing question is howOGTselects its substrates. Prior work has indicated that theN-terminaltetratricopeptide repeat (TPR) domain of OGT, rather than itsC-terminalcatalytic domain, is responsible forsubcellular targeting andsubstrate selection.An additional impetus for exploring the OGT TPR domain interactome is the fact that missense mutations inOGTassociated with X-linked intellectual disability (XLID) are primarily localized to the TPR domain without substantial impact on activity or stability of the enzyme.Therefore, we adapted theBioIDlabeling method to identify interactors of a TPR-BirA* fusion protein in HeLa cells. We identified 115high confidenceinteractors representing both known and novel O-GlcNAcmodified proteins and OGT interactors. The TPR interactors are highly enriched in processes in which OGT has a known role (e.g. chromatin remodeling, cellular survival of heat stress, circadian rhythm), as well as processesin which OGT has yet to be implicated (e.g. pre-mRNA processing). Importantly,the identified TPR interactors are involved in several disease states but most notably are highly enriched in pathologies featuring intellectual disability.Theseproteinsrepresent candidateinteractors that may underlie the mechanismby which mutations in OGT lead to XLID. Furthermore, the identified interactors provide additional evidence of the importance of the TPR domain for OGT targeting and/or substrate selection.Thus, this defined interactome for the TPR domain of OGT serves as ajumping off point for future researchexploringthe role of OGT, the TPR domain, and its protein interactorsin multiple cellular processes and disease mechanisms, including intellectual disability.

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“…S1 E and F). Therefore, we tested whether Pak2 overexpression promoted cellular senescence in normal human fibroblasts using an established senescence protocol (26). We transduced cells with a lentivirus encoding an empty vector, a vector expressing wild-type Pak2, and a vector expressing Pak2 (T402A) kinase dead mutant.…”

Section: Pak2 Expression Level Increases During Ois and Its Overexprmentioning

confidence: 99%

“…3C). We examined the deposition of newly synthesized H3.3 in senescent cells by performing the "quenchchase-pulse" SNAP labeling assay (26,30). We observed a dramatic loss of ectopic H3.3 expression upon HIRA depletion during senescence progression (Fig.…”

Section: Pak2 Expression Level Increases During Ois and Its Overexprmentioning

confidence: 99%

Pak2 kinase promotes cellular senescence and organismal aging

Lee

Gan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Cellular senescence defines an irreversible cell growth arrest state linked to loss of tissue function and aging in mammals. This transition from proliferation to senescence is typically characterized by increased expression of the cell-cycle inhibitor p16INK4a and formation of senescence-associated heterochromatin foci (SAHF). SAHF formation depends on HIRA-mediated nucleosome assembly of histone H3.3, which is regulated by the serine/threonine protein kinase Pak2. However, it is unknown if Pak2 contributes to cellular senescence. Here, we show that depletion of Pak2 delayed oncogene-induced senescence in IMR90 human fibroblasts and oxidative stress–induced senescence of mouse embryonic fibroblasts (MEFs), whereas overexpression of Pak2 accelerated senescence of IMR90 cells. Importantly, depletion of Pak2 in BubR1 progeroid mice attenuated the onset of aging-associated phenotypes and extended life span. Pak2 is required for expression of genes involved in cellular senescence and regulated the deposition of newly synthesized H3.3 onto chromatin in senescent cells. Together, our results demonstrate that Pak2 is an important regulator of cellular senescence and organismal aging, in part through the regulation of gene expression and H3.3 nucleosome assembly.

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O-linked N -acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence

Cited by 31 publications

References 77 publications

The sweet side of the cell cycle

The sweet side of the cell cycle

Generation of an Unbiased Interactome for the Tetratricopeptide Repeat Domain of O-GlcNAc Transferase Indicates a Role for the Enzyme in Intellectual Disability

Pak2 kinase promotes cellular senescence and organismal aging

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