The Protein Kinase Aurora-C Phosphorylates TRF2

Spengler, Daniel

doi:10.4161/cc.6.20.4781

Cited by 15 publications

(8 citation statements)

References 13 publications

(17 reference statements)

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“…It is reported that Aurora-C-T191D is hyperactive mutant and its relative activity is sevenfold higher than the activity of Aurora-C-WT [19]. But we report that Aurora-C-T191D is not hyperactive but is constitutively active and behaves exactly like its partner Aurora C-WT.…”

Section: Introductioncontrasting

confidence: 47%

Aurora kinase-C-T191D is constitutively active mutant

Khan

Attaullah

et al. 2012

BMC Cell Biol

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BackgroundAurora kinases (Aurora-A, B and C) belong to a family of conserved serine/threonine kinases which are key regulators of cell cycle progression. Aurora-A and Aurora-B are expressed in somatic cells and involved in cell cycle regulation while aurora-C is meiotic chromosome passenger protein. As Aurora kinase C is rarely expressed in normal somatic cells and has been found over expressed in many cancer lines. It is suggested that Aurora-C-T191D is not hyperactive mutant.ResultAurora-C-T191D variant form was investigated and compared with wild type. The overexpression of Aurora-C-T191D was observed that it behaves like Aurora-C wild type (aurC-WT). Both Aurora-C-T191D and aurC-WT induce abnormal cell division resulting in centrosome amplification and multinucleation in transiently transfected cells as well as in stable cell lines. Similarly, Aurora-C-T191D and aurC-WT formed foci of colonies when grown on soft agar, indicating that a gain of Aurora-C activity is sufficient to transform cells. Furthermore, we reported that NIH-3 T3 stable cell lines overexpressing Aurora-C-T191D and its wild type partner induced tumour formation when injected into nude mice, demonstrating the oncogenic activity of enzymatically active Aurora kinase C. Interestingly enough tumour aggressiveness was positively correlated with the rate of kinase activity, making Aurora-C a potential anti-cancer therapeutic target.ConclusionThese findings proved that Aurora C-T191D is not hyperactive but is constitutively active mutant.

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Section: Introductioncontrasting

confidence: 47%

Aurora kinase-C-T191D is constitutively active mutant

Khan

Attaullah

et al. 2012

BMC Cell Biol

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“…The structure of TIN2-TRF2-TPP1 shown here implies a potential regulatory mechanism for the stability of TIN2-TRF2 complex. Indeed, TRF2 T358 in the TIN2-binding motif is known to be phosphorylated by Aurora C [43]. Our crystal structure reveals that TRF2 T358 sits in an acidic pocket of TIN2 ( Figure 4A), and thus a negatively charged phosphate group deposited on T358 would weaken or disrupt the interaction between TIN2 and TRF2.…”

Section: Discussionmentioning

confidence: 89%

Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex

et al. 2017

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Telomeres are nucleoprotein complexes that play essential roles in protecting chromosome ends. Mammalian telomeres consist of repetitive DNA sequences bound by the shelterin complex. In this complex, the POT1-TPP1 heterodimer binds to single-stranded telomeric DNAs, while TRF1 and TRF2-RAP1 interact with double-stranded telomeric DNAs. TIN2, the linchpin of this complex, simultaneously interacts with TRF1, TRF2, and TPP1 to mediate the stable assembly of the shelterin complex. However, the molecular mechanism by which TIN2 interacts with these proteins to orchestrate telomere protection remains poorly understood. Here, we report the crystal structure of the N-terminal domain of TIN2 in complex with TIN2-binding motifs from TPP1 and TRF2, revealing how TIN2 interacts cooperatively with TPP1 and TRF2. Unexpectedly, TIN2 contains a telomeric repeat factor homology (TRFH)-like domain that functions as a protein-protein interaction platform. Structure-based mutagenesis analyses suggest that TIN2 plays an important role in maintaining the stable shelterin complex required for proper telomere end protection.

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“…Other mechanisms are also possible, including Chk2 phosphorylation of histone H3 and an inhibition of nucleosome remodeling during early S phase. Alternatively, TRF2 may be subject to other cell cycle controls, including its ability to be phosphorylated by the Aurora C kinase (37). How this transient inhibition of replication initiation enhances episome stability is not known.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Epstein-Barr Virus Origin of Plasmid Replication (OriP) by the S-Phase Checkpoint Kinase Chk2

Zhou

Deng

Norseen

et al. 2010

J Virol

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The Epstein-Barr virus (EBV) origin of plasmid replication (OriP) is required for episome stability during latent infection. Telomere repeat factor 2 (TRF2) binds directly to OriP and facilitates DNA replication and plasmid maintenance. Recent studies have found that TRF2 interacts with the DNA damage checkpoint protein Chk2. We show here that Chk2 plays an important role in regulating OriP plasmid stability, chromatin modifications, and replication timing. The depletion of Chk2 by small interfering RNA (siRNA) leads to a reduction in DNA replication efficiency and a loss of OriP-dependent plasmid maintenance. This corresponds to a change in OriP replication timing and an increase in constitutive histone H3 acetylation. We show that Chk2 interacts with TRF2 in the early G 1 /S phase of the cell cycle. We also show that Chk2 can phosphorylate TRF2 in vitro at a consensus acceptor site in the amino-terminal basic domain of TRF2. TRF2 mutants with a serine-to-aspartic acid phosphomimetic substitution mutation were reduced in their ability to recruit the origin recognition complex (ORC) and stimulate OriP replication. We suggest that the Chk2 phosphorylation of TRF2 is important for coordinating ORC binding with chromatin remodeling during the early S phase and that a failure to execute these events leads to replication defects and plasmid instability.Epstein-Barr virus (EBV) is a human herpesvirus that can persist as a multicopy episome in latently infected B lymphocytes (16,30). During latent infection, the viral genomes replicate once per cell cycle and utilize the cellular machinery required for chromosomal replication (6,10,22,31,32,41,43). One virally encoded protein, EBNA1, is required for OriPdependent DNA replication and plasmid maintenance (21, 44; reviewed in references 22 and 38). EBNA1 binds to a family of repeats (FR) and a dyad symmetry element (DS) within OriP (29). The FR confers plasmid maintenance and enhances replication initiation from the DS. The DS consists of two pairs of EBNA1 binding sites flanked by telomere repeat factor (TRF) binding sites (2,9,19,42). The DS has been shown to function similarly to cellular origins that replicate once per cell cycle and assemble a prereplication complex that includes the cellular origin recognition complex (ORC) and minichromosome maintenance (MCM) subunits (6,10,31,32).ORC recruitment to the DS is thought to play a key role in determining its function as an origin of DNA replication (3,14). TRF2, along with EBNA1, was shown previously to interact with ORC subunits and to recruit the ORC to the DS (1, 23, 27, 39). The ORC interaction domains in both TRF2 and EBNA1 appear to share an amino acid composition of basic residues, often referred to as arginine-glycine-glycine (RGG) motifs (17). The basic stretches have been implicated in the intermolecular linking activity of EBNA1 and are variably termed linking region 1 (LR1) and LR2 (25). LR1 and LR2 have AT-hook DNA binding activity and confer a metaphase chromosome attachment function to EBNA1, which are t...

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The Protein Kinase Aurora-C Phosphorylates TRF2

Cited by 15 publications

References 13 publications

Aurora kinase-C-T191D is constitutively active mutant

Aurora kinase-C-T191D is constitutively active mutant

Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex

Regulation of Epstein-Barr Virus Origin of Plasmid Replication (OriP) by the S-Phase Checkpoint Kinase Chk2

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