Phosphorylation and functions of the RNA polymerase II CTD

Phatnani, Hemali; Greenleaf, Arno L.

doi:10.1101/gad.1477006

Cited by 660 publications

(736 citation statements)

References 140 publications

(178 reference statements)

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“…We did not observe any significant change of H3K4m1 enrichment with or without IR (data not shown). In addition, ChIP analyses revealed positive enrichment of Ser5-phosphorylated polymerase II 49 at the R2 enhancer and confirmed the previous observation that only under the differentiation condition, polymerase II is recruited to the R2 enhancer 47 (Figure 4d). Although reduced enrichment of polymerase II was observed at R2 under the differentiation condition post IR, we could not draw any conclusions on its biological significance due to the background variation (Figure 4d, Differentiation, R2 versus background).…”

Section: Resultssupporting

confidence: 90%

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

et al. 2014

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Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging. Cell Death and Differentiation (2015) 22, 560-573; doi:10.1038/cdd.2014; published online 12 December 2014The tumor suppressor p53 promotes cell cycle arrest or apoptosis in response to diverse stress signals such as DNA damage, thus preventing propagation of genetically compromised cells. [1][2][3] Among the diverse functions attributed to p53, a growing body of evidence supports its role in regulation of differentiation and maintenance of cellular function and integrity. 1,[4][5][6][7] For example, p53 represses Nanog to maintain genetic stability of the stem cell pool by promoting differentiation of mouse embryonic stem cells (mESCs) after DNA damage. 6 Skeletal muscle differentiation, a key step during muscle tissue formation, is orchestrated by the MyoD family of myogenic regulatory factors (MRFs). MyoD determines the myogenic lineage, whereas myogenin, a member of the MRF family, functions downstream of MyoD and plays a critical role in driving terminal differentiation as myogenin-null mice show a lethal deficiency of differentiated skeletal muscle. [8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro. [15][16][17][18][19][20] In contrast, under stress-associated conditions such as inflammation, chronic exposure to double-strand DNA breaks, and aging, enhanced p53 activity has been shown to correlate with skeletal muscle atrophy in vivo. [21][22][23][24][25] In addition, it has been shown that p53 and its downstream effectors are required for an inflammatory cytokine-mediated inhibition of myogenic differentiation in vitro. 22 Int...

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Section: Resultssupporting

confidence: 90%

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

et al. 2014

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“…The repeated serine residues within the CTD are susceptible to phosphorylation [207]. The CTD is not observed in the structure of yeast PolII, suggesting that it may be flexible [208].…”

Section: The Ctd Of Poliimentioning

confidence: 99%

Protein factors in pre-mRNA 3′-end processing

Mandel

Bai

Tong

2007

Cell. Mol. Life Sci.

364

482

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Most eukaryotic mRNA precursors (pre-mRNAs) must undergo extensive processing, including cleavage and polyadenylation at the 3′-end. Processing at the 3′-end is controlled by sequence elements in the pre-mRNA (cis elements) as well as protein factors. Despite the seeming biochemical simplicity of the processing reactions, more than 14 proteins have been identified for the mammalian complex, and more than 20 proteins have been identified for the yeast complex. The 3′-end processing machinery also has important roles in transcription and splicing. The mammalian machinery contains several sub-complexes, including cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF), cleavage factor I (CF I m ), and cleavage factor II (CF II m ). Additional protein factors include poly(A) polymerase (PAP), poly(A) binding protein (PABP), symplekin, and the C-terminal domain (CTD) of RNA polymerase II largest subunit. The yeast machinery includes cleavage factor IA (CF IA), cleavage factor IB (CF IB), and cleavage and polyadenylation factor (CPF).

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“…The C-terminal domain (CTD) of RNA Pol II contains between 25 and 52 copies of a 7 amino acid repeat, Y 1 S 2 P 3 T 4 S 5 P 6 S 7 [27]. Phosphorylation of two of the serines, Ser2 and Ser5, is required for RNA processing, including the addition of the 5' CAP and 3' polyadenylation [28;29;30].…”

Section: Glucose Promotes and Ly294002 And Ly303511 Prevents The Recrmentioning

confidence: 99%

Detailed molecular analysis of the induction of the L-PK gene by glucose

Eckert

Zhang

Collier

et al. 2008

Biochemical and Biophysical Research Communications

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Glucose has powerful effects on gene expression and participates in the fasted to fed transition of the liver. However, the molecular mechanism of glucose-regulated gene expression has not been completely described. In the present study, we performed a detailed analysis of the molecular events of the insulin-independent glucose response of the liver-type pyruvate kinase (L-PK) gene. L-PK mRNA was increased by glucose at the transcriptional level as determined by real-time RT-PCR, mRNA stability measurements, and nuclear run-on assays. LY294002 and LY303511 inhibited the glucose response of the L-PK gene at the transcriptional level. Histones H3 and H4 associated with the L-PK gene promoter were hyperacetylated and HNF4α was constitutively bound in low and high glucose. Treatment with 20 mM glucose increased recruitment of ChREBP, additional HNF4α, and RNA polymerase II. Glucose stimulated the phosphorylation of the C terminal domain of RNA polymerase II, with increased Ser5 phosphorylation near the transcription start site and increased Ser2 phosphorylation near the termination signal. LY294002 and LY303511 blocked the recruitment of RNA polymerase II to the L-PK gene, reducing the rate of transcription. The results of these studies demonstrate fundamental details of the molecular mechanism of glucose activated gene expression.

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Phosphorylation and functions of the RNA polymerase II CTD

Cited by 660 publications

References 140 publications

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

Protein factors in pre-mRNA 3′-end processing

Detailed molecular analysis of the induction of the L-PK gene by glucose

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