Population declines and extinctions of amphibians have been attributed to the chytrid fungus Batrachochytrium dendrobatidis (Bd), especially one globally emerging recombinant lineage ('Bd-GPL'). We used PCR assays that target the ribosomal internal transcribed spacer region (ITS) of Bd to determine the prevalence and genetic diversity of Bd in South Korea, where Bd is widely distributed but is not known to cause morbidity or mortality in wild populations. We isolated Korean Bd strains from native amphibians with low infection loads and compared them to known worldwide Bd strains using 19 polymorphic SNP and microsatellite loci. Bd prevalence ranged between 12.5 and 48.0%, in 11 of 17 native Korean species, and 24.7% in the introduced bullfrog Lithobates catesbeianus. Based on ITS sequence variation, 47 of the 50 identified Korean haplotypes formed a group closely associated with a native Brazilian Bd lineage, separated from the Bd-GPL lineage. However, multilocus genotyping of three Korean Bd isolates revealed strong divergence from both Bd-GPL and the native Brazilian Bd lineages. Thus, the ITS region resolves genotypes that diverge from Bd-GPL but otherwise generates ambiguous phylogenies. Our results point to the presence of highly diversified endemic strains of Bd across Asian amphibian species. The rarity of Bd-GPL-associated haplotypes suggests that either this lineage was introduced into Korea only recently or Bd-GPL has been outcompeted by native Bd strains. Our results highlight the need to consider possible complex interactions among native Bd lineages, Bd-GPL and their associated amphibian hosts when assessing the spread and impact of Bd-GPL on worldwide amphibian populations.
Some HRV variables calculated from R-R interval series shorter than 5 min were well matched with those calculated from the 5-min R-R interval. Thus, ultra-short-term HRV is likely to be a good surrogate method to assess trends in HRV.
The multiprotein human TRAP/Mediator complex, which is phylogenetically related to the yeast SRB/ Mediator coactivator, facilitates activation through a wide variety of transcriptional activators. However, it remains unclear how TRAP/Mediator functions in the context of other coactivators. Here we have identified a previously uncharacterized integral subunit (TRAP25) of the complex that is apparently metazoan specific. An antibody that is specific for TRAP25 allowed quantitative immunodepletion of essentially all TRAP/Mediator components from HeLa nuclear extract, without detectably affecting levels of RNA polymerase II and corresponding general transcription factors. Surprisingly, the TRAP/Mediator-depleted nuclear extract displayed severely reduced levels of both basal and activator-dependent transcription from DNA templates. Both activities were efficiently restored upon readdition of purified TRAP/Mediator. Moreover, restoration of basal and activator-dependent transcription to extracts that were simultaneously depleted of TRAP/Mediator and TFIID (TBP plus the major TAF II s) required addition of both TBP and associated TAF II s, as well as TRAP/Mediator. These observations indicate that TAF II s and Mediator are jointly required for both basal and activated transcription in the context of a more physiological complement of nuclear proteins. We propose a close mechanistic linkage between these components that most likely operates at the level of combined effects on the general transcription machinery and, in addition, a direct role for Mediator in relaying activation signals to this machinery.Transcriptional regulation of eukaryotic protein-encoding genes requires the concerted function of distinct classes of factors (reviewed in reference 40). These include (i) RNA polymerase II (Pol II) and its associated general transcription factors (GTFs) (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH), which are sufficient for low levels of accurately initiated transcription from DNA templates in vitro (generally referred to as basal transcription), (ii) site-specific DNA-binding regulatory factors, and (iii) transcriptional cofactors, which mediate responsiveness of Pol II and GTFs to various activators and repressors. Cofactors (coactivators or corepressors) have been operationally defined as factors that, while exhibiting no intrinsic site-specific DNA binding, preferentially influence the function of DNA binding regulatory factors without affecting basal (regulatory factor-independent) transcription.Early biochemical studies employing metazoan systems reconstituted with partially purified factors pointed to TATA box-binding protein (TBP)-associated factors (TAF II s) in TFIID (7, 16, 37) and positive cofactors (PC1, PC2, PC3, and PC4) within the USA fraction (30) as coactivators required for the function of diverse activators on DNA templates (reviewed in references 4, 40, and 45). Parallel studies with Saccharomyces cerevisiae revealed the existence of a coactivator or Mediator (8) that interacts with Pol II to for...
Detection of low-affinity or transient interactions can be a bottleneck in our understanding of signaling networks. To address this problem, we developed an arrayed screening strategy based on protein complementation to systematically investigate protein-protein interactions in live human cells, and performed a large-scale screen for regulators of telomeres. Maintenance of vertebrate telomeres requires the concerted action of members of the Telomere Interactome, built upon the six core telomeric proteins TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. Of the ϳ12,000 human proteins examined, we identified over 300 proteins that associated with the six core telomeric pro- During mammalian DNA replication, linear chromosomal ends will gradually erode because of the inability of the DNA replication machinery to replicate the extreme 5Ј terminus of a linear DNA sequence (1, 2). This inherent "end replication problem" is circumvented through specialized chromosomal end structures (telomeres) and the action of the RNA-containing DNA polymerase -telomerase (3-9). Telomere homeostasis is essential for genome stability, cell survival, and growth.Telomeres and telomerase help to ensure genome integrity in eukaryotes by enabling complete replication of the ends of linear DNA molecules, and preventing chromosomal rearrangements or fusion. For dividing cells such as stem cells and the majority of cancer cells, the telomerase is an essential positive regulator of their telomere length and ultimately determines the proliferative potential of these cells.Mammalian telomeres consist of a series of (TTAGGG)n sequence repeats and terminate in 3Ј single-stranded DNA overhangs that are extendable by the telomerase (10). Exposed linear chromosome ends or naturally occurring doublestranded breaks pose additional risks including activation of DNA damage responses. The ends of telomeres in mammalian cells appear to fold back in a T-loop structure, with the 3Ј G-rich single-stranded overhang invading into the doublestranded telomere regions to form the D-loop (11). The structure of the telomeres, coupled with the coordinated action of a collection of proteins that protect the ends of chromosomes (12-15), contributes to the maintenance of telomere integrity, genome stability, and proper cell cycle progression.In mammals, the most widely studied telomere-associated proteins include the double-stranded DNA binding proteins TRF1 and TRF2 (16,17), the single-stranded telomeric DNA binding protein POT1 (18), and three associated factors (RAP1, TIN2, and TPP1) (19 -23). Work from our lab and others suggest that TPP1, along with POT1, TIN2, TRF1, TRF2, and RAP1, form a higher order complex (the telosome/ shelterin) at the telomeres (24 -27). Information regarding the state of the telomere ends can be transmitted from TRF1 and TRF2 to POT1, through TPP1 and the other subunits (28). Furthermore, TRF1 and TRF2 function as bona fide protein hubs and interact with a diverse array of factors/complexes that are involved in cell cycle, DNA repair, and recombinat...
An important step in the herpesvirus life cycle is the switch from latency to lytic reactivation. The RTA transcription activator of Kaposi's sarcoma-associated herpesvirus (KSHV) acts as a molecular switch for lytic reactivation. Here we demonstrate that KSHV RTA recruits CBP, the SWI/SNF chromatin remodeling complex, and the TRAP/Mediator coactivator into viral promoters through interactions with a short acidic sequence in the carboxyl region and that this recruitment is essential for RTA-dependent viral gene expression. The Brg1 subunit of SWI/SNF and the TRAP230 subunit of TRAP/Mediator were shown to interact directly with RTA. Consequently, genetic ablation of these interactions abolished KSHV lytic replication. These results demonstrate that the recruitment of CBP, SWI/SNF, and TRAP/Mediator complexes by RTA is the principal mechanism to direct well-controlled viral gene expression and thereby viral lytic reactivation.Regulation of cellular gene expression requires carefully choreographed binding by multiple transcription cofactors. A group of these cofactors are involved in the regulated alteration of chromatin structure, termed chromatin remodeling. These cofactors include the SWI/SNF complex, which disrupts nucleosomes in vitro and facilitates transcription factor binding in an ATP-dependent manner, and histone acetyltransferase and histone deacetylase, which act through covalent modification of histone tails (23,25,32,46). Several types of activators, including nuclear receptors, C/EBP, c-Myc protooncoprotein, and erythroid Krüppel-like factor (EKLF), have been shown to physically or functionally interact with SWI/ SNF complexes and histone acetyltransferase-histone deacetylase (3,11,24,31,44,47). Recent studies indicate that chromatin remodeling is not an inherent feature of transcriptional activators but rather an important event required for subsequent transcription preinitiation complex assembly or a defining step in the transcriptional initiation process.RNA polymerase II is found in a large holoenzyme complex containing several general transcription factors and the Mediator (32). Mediator is a large complex composed of polypeptides that range in size from 10 to 240 kDa. Several mammalian Mediator activities were discovered that specifically supported (TRAP/SMCC, ARC, DRIP, and Srb/Mediator) or repressed (NAT) the function of activators (30,32). This complex functions as an interface between sequence-specific transcription factors and the general transcriptional apparatus. For example, the TRAP complex interacts with p53, VP16, NF-B, and E1A to recruit RNA polymerase II and general transcription factors to form a functional preinitiation complex at the promoter (20). More specifically, the TRAP220 subunit of this complex is known to interact with nuclear receptors, including the thyroid receptor, vitamin D receptor, estrogen receptor, and glucocorticoid receptor; the TRAP150 subunit is likely an integrator of the E1A and RAS signaling pathways; and the TRAP80 subunit interacts directly with the ...
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