Mutational analysis defines a C-terminal tail domain of RAP1 essential for Telomeric silencing in Saccharomyces cerevisiae.

Liu, Cheng; Mao, Xiangdong; Lustig, Arthur J.

doi:10.1093/genetics/138.4.1025

Cited by 87 publications

(32 citation statements)

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“…The effects of mutations in RAP/and SIR genes implicate these gene products directly in the repression mechanism, possibly through physical interactions among these proteins (for review see Laurenson and Rine, 1992;Palladino and Gasser, 1994). For instance, deletions of 28 aa or more from the COOH terminus of RAP1 abrogate telomeric silencing (Kyrion et al, 1992;Liu et al, 1994). Point mutations within the COOH-terminal 20 aa of RAP1 have a similar effect, and certain of these missense mutations are suppressed by Sir3 overproduction, while the truncation alleles are not (Liu et al, 1994).…”

mentioning

confidence: 99%

The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing.

Cockell¹,

Palladino²,

Laroche³

et al. 1995

The Journal of Cell Biology

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174

172

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Abstract. The Silent Information Regulatory proteins,Sir3 and Sir4, and the telomeric repeat-binding protein RAP1 are required for the chromatin-mediated gene repression observed at yeast telomeric regions. All three proteins are localized by immunofluorescence staining to foci near the nuclear periphery suggesting a relationship between subnuclear localization and silencing. We present several lines of immunological and biochemical evidence that Sir3, Sir4, and RAP1 interact in intact yeast cells. First, immunolocalization of Sir3 to foci at the yeast nuclear periphery is lost in rapl mutants carrying deletions for either the terminal 28 or 165 amino acids of RAP1. Second, the perinuclear localization of both Sir3 and RAP1 is disrupted by overproduction of the COOH terminus of Sir4. Third, overproduction of the Sir4 COOH terminus alters the solubility properties of both Sir3 and full-length Sir4. Finally, we demonstrate that RAP1 and Sir4 coprecipitate in immune complexes using either anti-RAP1 or anti-Sir4 antibodies. We propose that the integrity of a tertiary complex between Sir4, Sir3, and RAP1 is involved in both the maintenance of telomeric repression and the clustering of telomeres in foci near the nuclear periphery.T HE regulation of gene expression by alterations in chromatin structure is a universal phenomenon in eukaryotic cells, and is responsible for the proper activation and inactivation of genes in the developmental program of multicellular organisms (Paro, 1993;Tartof and Bremer, 1990), for position effect variegation in flies (Eissenberg, 1989;Henikoff, 1990), and the variable expression of foreign genes integrated into chromosomes (e.g., Butner and Lo, 1986). In the yeast Saccharomyces cerevisiae, gene repression at the silent mating type loci (HML and HMR, collectively termed the HM loci) appears to involve a reduction in the accessibility of the entire domain to the transcription machinery, the yeast endonuclease HO, and to other modifying enzymes (for review see Laurenson and Rine, 1992). Similarly, the transcription of Pol II genes positioned adjacent to the poly(TGt.3) tracts at yeast telomeres was found to be metastable, switching between repressed and derepressed states in a process called telomeric position effect or silencing (Gottschling et al., 1990). Interestingly, like position effect variegation in Drosophila, where the condensed higher order structure of heterochromatin "spreads" into adjacent euchromatin, the transcriptionally inactive telomeric domain spreads inward from the telomere and is limited by the dosage of components involved in forming a "closed" chromatin state (Renauld et al., 1993; for review see Sandell and Zakian, 1992).The yeast system has provided the genetic means to identify trans-acting factors and cis-acting sequences required for both the metastable repression of gene expression in subtelomeric regions and the repression of mating type genes at HML and HMR. Both repression events are sensitive to mutations in many of the same genes, including SIR2, SIR3...

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mentioning

confidence: 99%

The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing.

Cockell¹,

Palladino²,

Laroche³

et al. 1995

The Journal of Cell Biology

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174

172

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“…Has a sequence-specific dsDNA binding activity Graham and Chambers, 1994;Konig et al, 1996 Nucleates the telomeric heterochromatic structure, essential for telomeric silencing Hardy et al, 1992;Kyrion et al, 1993;Liu et al, 1994;Cockell et al, 1995;Liu and Lustig, 1996 Suppresses NHEJ-mediated chromosome end-to-end fusions Pardo and Marcand, 2005 Suppresses telomerase-mediated telomere elongation Lustig et al, 1990;Kyrion et al, 1992;Marcand et al, 1997;Wotton and Shore, 1997 regions (Melville et al, 1999). In fact, two-thirds of the size polymorphisms are due to variations in subtelomeric regions, while chromosomal core regions, containing all essential genes, are relatively stable (Callejas et al, 2006).…”

Section: Scrap1mentioning

confidence: 99%

“…The functions of yeast RAP1 homologs in telomeric silencing and telomere length regulation have been extensively studied ( Lustig et al, 1990 , 1996 ; Hardy et al, 1992 ; Kyrion et al, 1992 , 1993 ; Liu et al, 1994 ; Cockell et al, 1995 ; Liu and Lustig, 1996 ; Marcand et al, 1997 ; Wotton and Shore, 1997 ; Kanoh and Ishikawa, 2001 ). In addition, Sc RAP1 prevents NHEJ-mediated telomere end-to-end fusions ( Pardo and Marcand, 2005 ).…”

Section: Maintaining Telomere/subteloemere Stability and Antigenic Variation In Trypanosoma Bruceimentioning

confidence: 99%

Keeping Balance Between Genetic Stability and Plasticity at the Telomere and Subtelomere of Trypanosoma brucei

2021

Front. Cell Dev. Biol.

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Telomeres, the nucleoprotein complexes at chromosome ends, are well-known for their essential roles in genome integrity and chromosome stability. Yet, telomeres and subtelomeres are frequently less stable than chromosome internal regions. Many subtelomeric genes are important for responding to environmental cues, and subtelomeric instability can facilitate organismal adaptation to extracellular changes, which is a common theme in a number of microbial pathogens. In this review, I will focus on the delicate and important balance between stability and plasticity at telomeres and subtelomeres of a kinetoplastid parasite, Trypanosoma brucei, which causes human African trypanosomiasis and undergoes antigenic variation to evade the host immune response. I will summarize the current understanding about T. brucei telomere protein complex, the telomeric transcript, and telomeric R-loops, focusing on their roles in maintaining telomere and subtelomere stability and integrity. The similarities and differences in functions and underlying mechanisms of T. brucei telomere factors will be compared with those in human and yeast cells.

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“…While Tb RAP1 knockdown led to profound derepression of all ES-linked silent VSGs [ 19 , 21 , 22 ], the molecular mechanism of this derepression is not completely understood. RAP1 homologs have been reported to repress the transcription of subtelomeric genes by strengthening the heterochromatic structure of the telomere [ 145 , 146 , 149 , 231 , 232 , 233 ]. Tb RAP1 also facilitates chromatin compaction at the telomere, at least in PF cells, and this appears to be a mechanism of Tb RAP1-mediated VSG silencing [ 20 ].…”

Section: Telomere Functions In Antigenic Variationmentioning

confidence: 99%

Regulation of Antigenic Variation by Trypanosoma brucei Telomere Proteins Depends on Their Unique DNA Binding Activities

Zhao

2021

Pathogens

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Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, Variant Surface Glycoprotein (VSG), to evade the host immune response. Such antigenic variation is a key pathogenesis mechanism that enables T. brucei to establish long-term infections. VSG is expressed exclusively from subtelomere loci in a strictly monoallelic manner, and DNA recombination is an important VSG switching pathway. The integrity of telomere and subtelomere structure, maintained by multiple telomere proteins, is essential for T. brucei viability and for regulating the monoallelic VSG expression and VSG switching. Here we will focus on T. brucei TRF and RAP1, two telomere proteins with unique nucleic acid binding activities, and summarize their functions in telomere integrity and stability, VSG switching, and monoallelic VSG expression. Targeting the unique features of TbTRF and TbRAP1′s nucleic acid binding activities to perturb the integrity of telomere structure and disrupt VSG monoallelic expression may serve as potential therapeutic strategy against T. brucei.

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Mutational analysis defines a C-terminal tail domain of RAP1 essential for Telomeric silencing in Saccharomyces cerevisiae.

Cited by 87 publications

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The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing.

The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing.

Keeping Balance Between Genetic Stability and Plasticity at the Telomere and Subtelomere of Trypanosoma brucei

Regulation of Antigenic Variation by Trypanosoma brucei Telomere Proteins Depends on Their Unique DNA Binding Activities

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