Regulation of ATR-dependent pathways by the FHA domain containing protein SNIP1

Roche, Kevin C; Rocha, Sónia; Bracken, Cameron P.; Perkins, Neil D.

doi:10.1038/sj.onc.1210233

Cited by 17 publications

(17 citation statements)

References 25 publications

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“…Finally, the FHA-domain-containing protein SNIP1 has recently been shown to interact with Drosha and play a role miRNA biogenesis 83. SNIP1 has documented roles in transcription regulation84,85 and is a component of a large SNIP1/SkIP-associated complex that is involved in cotranscriptional pre-mRNA processing 86. The ability of SNIP1 to recruit several proteins to active chromosomal loci86 suggests it could also recruit Drosha to sites of pri-miRNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

Subnuclear compartmentalization of transiently expressed polyadenylated pri-microRNAs: Processing at transcription sites or accumulation in SC35 foci

Pawlicki¹,

Steitz²

2009

Cell Cycle

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MicroRNAs (miRNAs) are small, noncoding RNAs that posttranscriptionally regulate expression of their target messenger RNAs.We recently demonstrated that primary miRNA transcripts (primiRNAs) retained at transcription sites are processed with enhanced efficiency, suggesting that pri-miRNA processing is coupled to transcription in mammalian cells. We also observed that transiently expressed pri-miRNAs accumulate in nuclear foci with splicing factor SC35 and Microprocessor components, Drosha and DGCR8. Here, we show that pri-miRNAs containing a self-cleaving hepatitis delta ribozyme accumulate in the nucleoplasm after release from their transcription sites, but are not efficiently processed. Pri-miRNAs with ribozyme-generated 3' ends do not localize to SC35-containing foci, whereas cleaved and polyadenylated pri-miRNA transcripts with or without the pre-miRNA hairpin do. Pri-miRNA/SC35 foci contain a number of proteins normally associated with SC35 domains, including ASF/SF2, PABII, and the prolyl isomerase, Pin1. In contrast, RNA polymerase II and PM/Scl-100 do not strongly colocalize with pri-miRNAs in SC35-containing foci. These data argue that pri-miRNA/SC35-containing foci are not major sites of pri-miRNA processing and that pri-miRNA processing is coupled to transcription. We discuss the implications of our findings relative to recent insights into miRNA biogenesis, mRNA metabolism, and the nuclear organization of gene expression.

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Section: Discussionmentioning

confidence: 99%

Subnuclear compartmentalization of transiently expressed polyadenylated pri-microRNAs: Processing at transcription sites or accumulation in SC35 foci

Pawlicki¹,

Steitz²

2009

Cell Cycle

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“…ATR can bind to UV-damaged DNA, and this DNA can stimulate ATR activity in a partially reconstituted system17, 48, 74. Finally, there are still a number of other proteins that have been implicated in ATR regulation through as yet undefined mechanisms including PP5, p18, and SNIP175–77. Some of these regulatory activities could help produce or maintain the checkpoint-activating nucleic acid structure78.…”

Section: Mechanisms Of Atr Activationmentioning

confidence: 99%

ATR: an essential regulator of genome integrity

Cimprich

Chen

2008

Nat Rev Mol Cell Biol

1,586

1,800

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PrefaceGenome maintenance is a constant problem in all cells and a coordinated response to DNA damage is required to maintain cellular viability and prevent disease. The ATR and ATM protein kinases are master regulators of the DNA damage response, signaling to control cell cycle transitions, DNA replication, DNA repair, and apoptosis. Recent studies have provided insights into the mechanisms controlling ATR activation, helped to explain the overlapping but non-redundant activities of ATR and ATM in DNA damage signaling, and clarified the critical functions of ATR in maintaining genome integrity. IntroductionAll cells have elaborate mechanisms to maintain their genomes. DNA can be damaged during replication, by reactive metabolic byproducts as well as environmental mutagens. Responding to and repairing DNA damage is critical for cell viability and disease prevention.The DNA damage response (DDR) is a signal transduction pathway that coordinates cell cycle transitions, DNA replication, DNA repair and apoptosis. The major regulators of the DDR are the phosphoinositide 3-kinase related protein kinases (PIKKs), including ataxia-telangiectasia mutated (ATM) and ATM and Rad3 related (ATR). ATM and ATR share many biochemical and functional similarities. Both are large kinases with significant sequence homology and a strong preference to phosphorylate serine or threonine residues that are followed by glutamine. Both target an overlapping set of substrates that promote cell cycle arrest and DNA repair. However, ATR is essential for the viability of replicating human and mouse cells, whereas ATM is not 1-3 . ATM functions in response to rare occurrences of double strand breaks. By contrast, ATR is activated during every S-phase to regulate the firing of replication origins, the repair of damaged replication forks and to prevent the premature onset of mitosis 4, 5 (Fig. 1).Mutations in ATM predispose carriers to cancer and are found in approximately 0.5-1% of the population 6, 7 . People with mutations in both alleles of ATM suffer from the neurodegenerative and cancer predisposition disorder ataxia-telangiectasia 8 . Mutations in ATR are rare and probably only compatible with viability when heterozygous or hypomorphic. While the only clear link between ATR gene mutation and disease is in a few patients with the rare Seckel syndrome (characterized by growth retardation and microcephaly) 9 , disruptions in the ATR pathway do cause genomic instability, and ATR is activated by most cancer chemotherapies. Furthermore, ATR signaling is a promising target for cancer drug development 10, 11 . This review will focus on ATR signaling in the DNA damage response, and compare and contrast it with the more specialized role of ATM. NIH Public Access Mechanisms of ATR ActivationThe broad functions and physiological importance of ATR derive in large part from recognizing the signals that lead to its activation versus that of ATM. Thus, we will address the mechanism of activation in some detail. Recognizing DNA damageAlthough ATR is activ...

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“…229 SNIP1 also controls p53 expression in response to UV stress and modulates the activity of the DNA-damage ATR kinase on numerous stress-related targets including p53. 230 Moreover, SKIP splicing activity is also involved in CDKNA1/p21 cip exon splicing during p53-dependent DNA-damage stress response. 231 In this case, the spliceosome U2AF65 factor is specifically recruited by SKIP on the p21 cip gene in proximity to an elongation RNA pol-II pause site where it binds the nascent and unspliced premRNA and favors subsequent splicing.…”

Section: Alternative Rna Splicing and Crosstalk Of Wnt Signalingmentioning

confidence: 99%

Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials

Mao

Byers

2011

Crit Rev Eukar Gene Expr

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Wnt signaling controls cell specification and fate during development and adult tissue homeostasis by converging on a small family of DNA binding factors, the T-cell factor/lymphoid enhancer factor (TCF/LEF) family. In response to Wnt signals, TCF/LEF members undergo a transcriptional switch from repression to activation mediated in part by nuclear β-catenin binding and recruitment of co-activator complexes. In mammals, the specificity and fine tuning of this transcriptional switch is also achieved by the cell-context-dependent expression of four members (TCF7, TCF7L1, TCF7L2, and LEF1) and numerous variants, which display differential DNA binding affinity and specificity, repression strength, activation potential, and regulators. TCF7/LEF1 variants are generated by alternative promoters, alternative exon cassettes, and alternative donor/acceptor splicing sites, allowing combinatorial insertion/exclusion of modular functional and regulatory domains. In this review we present mounting evidence for the interdependency of TCF7/LEF1 variant expression and functions with cell lineage and cell state. We also illustrate how the p53 and nuclear receptor family of transcription factors, known to control cell fate and to inhibit Wnt signaling, may participate in the fine tuning of TCF7/LEF1 repression/activation potentials.

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Regulation of ATR-dependent pathways by the FHA domain containing protein SNIP1

Cited by 17 publications

References 25 publications

Subnuclear compartmentalization of transiently expressed polyadenylated pri-microRNAs: Processing at transcription sites or accumulation in SC35 foci

Subnuclear compartmentalization of transiently expressed polyadenylated pri-microRNAs: Processing at transcription sites or accumulation in SC35 foci

ATR: an essential regulator of genome integrity

Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials

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