The Nuclear Protein ALY Binds to and Modulates the Activity of Transcription Factor E2F2

Osinalde, Nerea; Olea, Miguel; Mitxelena, Jone; Aloria, Kerman; Rodriguez, José Antonio; Fullaondo, Asier; Arizmendi, Jesús M.; Zubiaga, Ana M.

doi:10.1074/mcp.m112.024158

Cited by 15 publications

(17 citation statements)

References 47 publications

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“…More recently, work from Osinalde et al. identified REF/Aly as an E2F2-interacting protein, and a modulator of E2F2-responsive genes ( 72 ). In their microarray analysis REF/Aly was found to influence the expression of ∼400 genes.…”

Section: Discussionmentioning

confidence: 99%

Depletion of REF/Aly alters gene expression and reduces RNA polymerase II occupancy

Stubbs

Conrad

2014

Nucleic Acids Research

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Pre-mRNA processing is mechanistically linked to transcription with RNA pol II serving as a platform to recruit RNA processing factors to nascent transcripts. The TREX complex member, REF/Aly, has been suggested to play roles in transcription and nuclear RNA stability in addition to its more broadly characterized role in mRNA export. We employed RNA-seq to identify a subset of transcripts with decreased expression in both nuclear and cytoplasmic fractions upon REF/Aly knockdown, which implies that REF/Aly affects their expression upstream of its role in mRNA export. Transcription inhibition experiments and metabolic labeling assays argue that REF/Aly does not affect stability of selected candidate transcripts. Instead, ChIP assays and nuclear run-on analysis reveal that REF/Aly depletion diminishes the transcription of these candidate genes. Furthermore, we determined that REF/Aly binds directly to candidate transcripts, supporting a direct effect of REF/Aly on candidate gene transcription. Taken together, our data suggest that the importance of REF/Aly is not limited to RNA export, but that REF/Aly is also critical for gene expression at the level of transcription. Our data are consistent with the model that REF/Aly is involved in linking splicing with transcription efficiency.

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Section: Discussionmentioning

confidence: 99%

Depletion of REF/Aly alters gene expression and reduces RNA polymerase II occupancy

Stubbs

Conrad

2014

Nucleic Acids Research

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“…ALYREF is significant in the S and G2 phases where its expression seems co-ordinated with that of Cyclin A [67]. ALYREF also represses the activity of the E2F2 transcription factor when bound to the CHK1 promoter, preventing the expression of the CHK1 checkpoint kinase that induces cell cycle arrest and checkpoint activation [164]. Furthermore, DDX39B and THOC2 may play a role in chromosome alignment [165] and spindle assembly [166], though whether these are direct effects or indirect through failure to export crucial mRNAs remains unclear.…”

Section: Biological Roles Of Trexmentioning

confidence: 99%

The role of TREX in gene expression and disease

Heath

Viphakone

Wilson

2016

Biochemical Journal

177

222

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TRanscription and EXport (TREX) is a conserved multisubunit complex essential for embryogenesis, organogenesis and cellular differentiation throughout life. By linking transcription, mRNA processing and export together, it exerts a physiologically vital role in the gene expression pathway. In addition, this complex prevents DNA damage and regulates the cell cycle by ensuring optimal gene expression. As the extent of TREX activity in viral infections, amyotrophic lateral sclerosis and cancer emerges, the need for a greater understanding of TREX function becomes evident. A complete elucidation of the composition, function and interactions of the complex will provide the framework for understanding the molecular basis for a variety of diseases. This review details the known composition of TREX, how it is regulated and its cellular functions with an emphasis on mammalian systems.

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“…ORF57 interacts with Aly/REF (12,14,17,18), a ubiquitously expressed nuclear protein which functions as a molecular chaperone to regulate dimerization, DNA binding, and transcriptional activity of basic region-leucine zipper (bZIP) proteins (19,20). It …”

Section: Importancementioning

confidence: 99%

“…Although all ORF57 functions involve ORF57 association with an RNA target, this association also requires cellular proteins to function as ORF57 cofactors (14,15), and each of the ORF57-specific functions depends on a specific cofactor(s). This has been demonstrated by the observation that ORF57 stabilizes PAN RNA via interaction with PABPC1 (16), that ORF57 mediates K8 splicing by interaction with SRSF3 (7), that ORF57 enhances ORF59 expression by the suppression of SPEN-induced nuclear hyperpolyadenylation (4), and that ORF57 promotes vIL-6 translation by preventing Ago2, a major component of RISC complexes, from interacting with a microRNA binding site in vIL-6 RNA (6).ORF57 interacts with Aly/REF (12,14,17,18), a ubiquitously expressed nuclear protein which functions as a molecular chaperone to regulate dimerization, DNA binding, and transcriptional activity of basic region-leucine zipper (bZIP) proteins (19,20). It …”

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confidence: 99%

Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization

Majerčiak

Pripuzova

Chan

et al. 2015

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 plays an essential role in KSHV lytic infection by promoting viral gene expression at the posttranscriptional level. Using bioinformatic and biochemical approaches, we determined that ORF57 contains two structurally and functionally distinct domains: a disordered nonstructural N-terminal domain (amino acids [aa] 1 to 152) and a structured ␣-helix-rich C-terminal domain (aa 153 to 455). The N-terminal domain mediates ORF57 interaction with several RNA-protein complexes essential for ORF57 to function. The N-terminal phosphorylation by cellular casein kinase II (CKII) at S21, T32, and S43, and other cellular kinases at S95 and S97 residues in proximity of the caspase-7 cleavage site, 30-DETD-33, inhibits caspase-7 digestion of ORF57. The structured C-terminal domain mediates homodimerization of ORF57, and the critical region for this function was mapped carefully to ␣-helices 7 to 9. Introduction of point mutations into ␣-helix 7 at ORF57 aa 280 to 299, a region highly conserved among ORF57 homologues from other herpesviruses, inhibited ORF57 homodimerization and led to proteasome-mediated degradation of ORF57 protein. Thus, homodimerization of ORF57 via its C terminus prevents ORF57 from degrading and allows two structure-free N termini of the dimerized ORF57 to work coordinately for host factor interactions, leading to productive KSHV lytic infection and pathogenesis. IMPORTANCEKSHV is a human oncogenic virus linked to the development of several malignancies. KSHV-mediated oncogenesis requires both latent and lytic infection. The KSHV ORF57 protein is essential for KSHV lytic replication, as it regulates the expression of viral lytic genes at the posttranscriptional level. This report provides evidence that the structural conformation of the ORF57 protein plays a critical role in regulation of ORF57 stability. Phosphorylation by CKII on the identified serine/threonine residues at the N-terminal unstructured domain of ORF57 prevents its digestion by caspase-7. The C-terminal domain of ORF57, which is rich in ␣-helices, contributes to homodimerization of ORF57 to prevent proteasome-mediated protein degradation. Elucidation of the ORF57 structure not only enables us to better understand ORF57 stability and functions but also provides an important tool for us to modulate ORF57's activity with the aim to inhibit KSHV lytic replication. K aposi's sarcoma-associated herpesvirus (KSHV) ORF57 (also known as Mta) is expressed early in the KSHV lytic cycle and is required for the efficient expression of a subset of viral genes, including KSHV PAN, ORF59, K8, viral interleukin-6 (vIL-6), ORF47, and others (1-7). A KSHV genome lacking ORF57 expression is associated with a defective lytic cycle incapable of producing infectious virions (8, 9).KSHV ORF57 functions as a posttranscriptional regulator of viral gene expression by affecting RNA stability (PAN, ORF59, and ORF47), splicing (ORF50 and K8), polyadenylation (ORF59), and translation (vIL-6) (1, 2, 4-7, 10) but ...

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The Nuclear Protein ALY Binds to and Modulates the Activity of Transcription Factor E2F2

Cited by 15 publications

References 47 publications

Depletion of REF/Aly alters gene expression and reduces RNA polymerase II occupancy

Depletion of REF/Aly alters gene expression and reduces RNA polymerase II occupancy

The role of TREX in gene expression and disease

Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization

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