Targeted Disruption of the GAS41 Gene Encoding a Putative Transcription Factor Indicates That GAS41 Is Essential for Cell Viability

Zimmermann, Katrin; Ahrens, Katja; Matthes, Siegfried; Buerstedde, Jean-Marie; Strätling, Wolf H.; Phi‐van, Loc

doi:10.1074/jbc.m200572200

Cited by 29 publications

(21 citation statements)

References 36 publications

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“…First identified and isolated in the glioblastoma multiforme cell line TX3868, YEATS4 is a highly conserved nuclear protein essential for cell viability that is frequently amplified in gliomas, astrocytomas and liposarcomas (29, 31, 38). A member of a protein family characterized by the presence of an N-terminal YEATS domain, YEATS4 shares high homology with transcription factor family members AF-9 and ENL (39).…”

Section: Discussionmentioning

confidence: 99%

YEATS4 Is a Novel Oncogene Amplified in Non–Small Cell Lung Cancer That Regulates the p53 Pathway

et al. 2013

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Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells (HBECs). Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis.

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Section: Discussionmentioning

confidence: 99%

YEATS4 Is a Novel Oncogene Amplified in Non–Small Cell Lung Cancer That Regulates the p53 Pathway

et al. 2013

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“…Several subunits of the NuA4 complex, including Tra1, Esa1, Arp4, and God1, are essential for yeast cell viability, whereas Yaf9 is dispensable under normal cell growth conditions (30). In contrast, GAS41 is essential for cell viability since targeted disruption of the gene in chicken cells causes cell death (49). A milder GAS41 knockdown through siRNA also revealed a growth arrest phenotype in HeLa cells, demonstrating that GAS41 is essential for cell growth and survival (23).…”

Section: Discussionmentioning

confidence: 99%

“…All of these proteins are involved in transcriptional regulation through multisubunit complexes. GAS41 is essential for cell survival and growth and is found as a subunit of the human TIP60 (16,23,49) and SRCAP (7) complexes. Yaf9, a yeast ortholog of GAS41, is a common subunit of both the yeast NuA4 HAT complex and the yeast SWR1 chromatin-modifying complex and is required for resistance to UV, DNA-damaging agents, and spindle stress in yeast (30,48).…”

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confidence: 99%

GAS41 Is Required for Repression of the p53 Tumor Suppressor Pathway during Normal Cellular Proliferation

Park

Roeder

2006

Molecular and Cellular Biology

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GAS41 is a common subunit of the TIP60 and SRCAP complexes and is essential for cell growth and viability. Here, we report that GAS41 is required for repression of the p53 tumor suppressor pathway during normal cellular proliferation. Either GAS41 small interfering RNA-mediated knockdown of GAS41 expression or specific interruptions of the carboxy-terminal coiled-coil motif of the GAS41 protein activate the p53 tumor suppressor pathway, as evidenced by p53 up-regulation, p53 serine-15 phosphorylation, and p21 transcriptional activation. Activation of the p53 pathway does not result from changes in TIP60 complex assembly or TIP60 coactivator functions for p53, since a TIP60 complex containing a coiled-coil mutant of GAS41 retains the same composition and histone acetyltransferase activity as its wild-type counterpart and since mutant GAS41 does not compromise ectopic p53-dependent transcriptional activation in a reporter gene assay. Finally, we demonstrate that GAS41 is prebound to the promoters of two p53 tumor suppressor pathway genes (p21 and p14 ARF ) in normal unstressed cells but is dissociated from both promoters in response to stress signals that activate p53. Our data suggest that GAS41 plays a role in repressing the p53 tumor suppressor pathway during the normal cell cycle by a TIP60-independent mechanism.Epigenetic mechanisms are now widely accepted as important regulators of gene expression (9, 19). Eucaryotic DNA is packaged into a chromatin structure that consists of arrays of core histone-containing nucleosomes organized, along with linker histone H1, into higher-order structures. Tightly packed nucleosomes generate an inherently repressive structure for gene expression by restricting access of various transcription factors and the general transcription machinery. Moreover, DNA modifications, such as CpG island methylation, and histone tail modifications, such as acetylation, methylation, phosphorylation, and ubiquitylation, allow complex epigenetic controls of nuclear activities that include DNA replication, transcription, DNA repair, and recombination (41).The increasingly large group of chromatin-modifying complexes contains enzymatic activities that covalently modify histone tails. The enzymatic subunits of complexes with histone acetyltransferase (HAT) activity include the H3 HAT GCN5 in Saccharomyces cerevisiae SAGA and human STAGA complexes and the H4 HAT Esa1 in the yeast NuA4 complex (1,22,35). In humans, a NuA4-like complex with TIP60 as the H4 HAT has been described, although there is also a similar complex that lacks HAT activity but shares the TRRAP, p400, Epc1, TIP49, TIP48, BAF53, and ␤-actin components (21, 24). It is not clear whether the last complex has a distinct function or whether it represents an intermediate in the assembly of the TIP60-containing complex. The TIP60 complex was proposed to play a role in DNA repair and apoptosis, and its largest subunit, TRRAP, has been implicated in p53-dependent mdm2 transcriptional activation (3,24,27). TIP60 also has been proposed as an ...

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“…2C). New proteins identified by mass spectrometry include GAS41, a protein related to AF9/ ENL leukemogenic factors, amplified in early glioma, and essential for cell viability (16,65) (Fig. 2C).…”

Section: Human Tip60 and Its Splice Variant Tip60b/plip Are Homologoumentioning

confidence: 99%

Structural and Functional Conservation of the NuA4 Histone Acetyltransferase Complex from Yeast to Humans

Doyon

Selleck

Lane

et al. 2004

Molecular and Cellular Biology

518

526

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The NuA4 histone acetyltransferase (HAT) multisubunit complex is responsible for acetylation of histone H4 and H2A N-terminal tails in yeast. Its catalytic component, Esa1, is essential for cell cycle progression, gene-specific regulation and has been implicated in DNA repair. Almost all NuA4 subunits have clear homologues in higher eukaryotes, suggesting that the complex is conserved throughout evolution to metazoans. We demonstrate here that NuA4 complexes are indeed present in human cells. Tip60 and its splice variant Tip60b/PLIP were purified as stable HAT complexes associated with identical polypeptides, with 11 of the 12 proteins being homologs of yeast NuA4 subunits. This indicates a highly conserved subunit composition and the identified human proteins underline the role of NuA4 in the control of mammalian cell proliferation. ING3, a member of the ING family of growth regulators, links NuA4 to p53 function which we confirmed in vivo. Proteins specific to the human NuA4 complexes include ruvB-like helicases and a bromodomain-containing subunit linked to ligand-dependent transcription activation by the thyroid hormone receptor. We also demonstrate that subunits MRG15 and DMAP1 are present in distinct protein complexes harboring histone deacetylase and SWI2-related ATPase activities, respectively. Finally, analogous to yeast, a recombinant trimeric complex formed by Tip60, EPC1, and ING3 is sufficient to reconstitute robust nucleosomal HAT activity in vitro. In conclusion, the NuA4 HAT complex is highly conserved in eukaryotes, in which it plays primary roles in transcription, cellular response to DNA damage, and cell cycle control.

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Targeted Disruption of the GAS41 Gene Encoding a Putative Transcription Factor Indicates That GAS41 Is Essential for Cell Viability

Cited by 29 publications

References 36 publications

YEATS4 Is a Novel Oncogene Amplified in Non–Small Cell Lung Cancer That Regulates the p53 Pathway

YEATS4 Is a Novel Oncogene Amplified in Non–Small Cell Lung Cancer That Regulates the p53 Pathway

GAS41 Is Required for Repression of the p53 Tumor Suppressor Pathway during Normal Cellular Proliferation

Structural and Functional Conservation of the NuA4 Histone Acetyltransferase Complex from Yeast to Humans

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