Publications by authors named "Hung-Ji Tsai"

16 Publications

  • Page 1 of 1

Neutralizing IFNL3 Autoantibodies in Severe COVID-19 Identified Using Molecular Indexing of Proteins by Self-Assembly.

bioRxiv 2021 Mar 3. Epub 2021 Mar 3.

Unbiased antibody profiling can identify the targets of an immune reaction. A number of likely pathogenic autoreactive antibodies have been associated with life-threatening SARS-CoV-2 infection; yet, many additional autoantibodies likely remain unknown. Here we present Molecular Indexing of Proteins by Self Assembly (MIPSA), a technique that produces ORFeome-scale libraries of proteins covalently coupled to uniquely identifying DNA barcodes for analysis by sequencing. We used MIPSA to profile circulating autoantibodies from 55 patients with severe COVID-19 against 11,076 DNA-barcoded proteins of the human ORFeome library. MIPSA identified previously known autoreactivities, and also detected undescribed neutralizing interferon lambda 3 (IFN-λ3) autoantibodies. At-risk individuals with anti-IFN-λ3 antibodies may benefit from interferon supplementation therapies, such as those currently undergoing clinical evaluation.

One-sentence Summary: Molecular Indexing of Proteins by Self Assembly (MIPSA) identifies neutralizing IFNL3 autoantibodies in patients with severe COVID-19.
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http://dx.doi.org/10.1101/2021.03.02.432977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941622PMC
March 2021

A Double-Edged Sword: Aneuploidy is a Prevalent Strategy in Fungal Adaptation.

Genes (Basel) 2019 10 10;10(10). Epub 2019 Oct 10.

Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.

Aneuploidy, a deviation from a balanced genome by either gain or loss of chromosomes, is generally associated with impaired fitness and developmental defects in eukaryotic organisms. While the general physiological impact of aneuploidy remains largely elusive, many phenotypes associated with aneuploidy link to a common theme of stress adaptation. Here, we review previously identified mechanisms and observations related to aneuploidy, focusing on the highly diverse eukaryotes, fungi. Fungi, which have conquered virtually all environments, including several hostile ecological niches, exhibit widespread aneuploidy and employ it as an adaptive strategy under severe stress. Gambling with the balance between genome plasticity and stability has its cost and in fact, most aneuploidies have fitness defects. How can this fitness defect be reconciled with the prevalence of aneuploidy in fungi? It is likely that the fitness cost of the extra chromosomes is outweighed by the advantage they confer under life-threatening stresses. In fact, once the selective pressures are withdrawn, aneuploidy is often lost and replaced by less drastic mutations that possibly incur a lower fitness cost. We discuss representative examples across hostile environments, including medically and industrially relevant cases, to highlight potential adaptive mechanisms in aneuploid yeast.
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http://dx.doi.org/10.3390/genes10100787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826469PMC
October 2019

Hypo-osmotic-like stress underlies general cellular defects of aneuploidy.

Nature 2019 06 8;570(7759):117-121. Epub 2019 May 8.

Center for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Aneuploidy, which refers to unbalanced chromosome numbers, represents a class of genetic variation that is associated with cancer, birth defects and eukaryotic micro-organisms. Whereas it is known that each aneuploid chromosome stoichiometry can give rise to a distinct pattern of gene expression and phenotypic profile, it remains a fundamental question as to whether there are common cellular defects that are associated with aneuploidy. Here we show the existence in budding yeast of a common aneuploidy gene-expression signature that is suggestive of hypo-osmotic stress, using a strategy that enables the observation of common transcriptome changes of aneuploidy by averaging out karyotype-specific dosage effects in aneuploid yeast-cell populations with random and diverse chromosome stoichiometry. Consistently, aneuploid yeast exhibited increased plasma-membrane stress that led to impaired endocytosis, and this defect was also observed in aneuploid human cells. Thermodynamic modelling showed that hypo-osmotic-like stress is a general outcome of the proteome imbalance that is caused by aneuploidy, and also predicted a relationship between ploidy and cell size that was observed in yeast and aneuploid cancer cells. A genome-wide screen uncovered a general dependency of aneuploid cells on a pathway of ubiquitin-mediated endocytic recycling of nutrient transporters. Loss of this pathway, coupled with the endocytic defect inherent to aneuploidy, leads to a marked alteration of intracellular nutrient homeostasis.
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http://dx.doi.org/10.1038/s41586-019-1187-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583789PMC
June 2019

Autonomously Replicating Linear Plasmids That Facilitate the Analysis of Replication Origin Function in .

mSphere 2019 03 6;4(2). Epub 2019 Mar 6.

School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Ramat Aviv, Israel

The ability to generate autonomously replicating plasmids has been elusive in , a prevalent human fungal commensal and pathogen. Instead, plasmids generally integrate into the genome. Here, we assessed plasmid and transformant properties, including plasmid geometry, transformant colony size, four selectable markers, and potential origins of replication, for their ability to drive autonomous plasmid maintenance. Importantly, linear plasmids with terminal telomere repeats yielded many more autonomous transformants than circular plasmids with the identical sequences. Furthermore, we could distinguish (by colony size) transient, autonomously replicating, and chromosomally integrated transformants (tiny, medium, and large, respectively). and a heterologous marker, yielded many transient transformants indicative of weak origin activity; the replication of the plasmid carrying the heterologous marker was highly dependent upon the addition of a origin sequence. Several chromosomal origins, with an origin fragment of ∼100 bp as well as a heterologous origin, , from , drove autonomous replication, yielding moderate transformation efficiency and plasmid stability. Thus, maintains linear plasmids that yield high transformation efficiency and are maintained autonomously in an origin-dependent manner. Circular plasmids are important tools for molecular manipulation in model fungi such as baker's yeast, yet, in , an important yeast pathogen of humans, prior studies were not able to generate circular plasmids that were autonomous (duplicated without inserting themselves into the chromosome). Here, we found that linearizing circular plasmids with sequences from telomeres, the chromosome ends, allows the plasmids to duplicate and segregate in We used this system to identify chromosomal sequences that facilitate the initiation of plasmid replication (origins) and to show that an ∼100-bp fragment of a origin and an origin sequence from a distantly related yeast can both function as origins in Thus, the requirements for plasmid geometry, but not necessarily for origin sequences, differ between and baker's yeast.
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http://dx.doi.org/10.1128/mSphere.00103-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403455PMC
March 2019

Cellular Stress Associated with Aneuploidy.

Dev Cell 2018 02;44(4):420-431

Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address:

Aneuploidy, chromosome stoichiometry that deviates from exact multiples of the haploid compliment of an organism, exists in eukaryotic microbes, several normal human tissues, and the majority of solid tumors. Here, we review the current understanding about the cellular stress states that may result from aneuploidy. The topics of aneuploidy-induced proteotoxic, metabolic, replication, and mitotic stress are assessed in the context of the gene dosage imbalance observed in aneuploid cells. We also highlight emerging findings related to the downstream effects of aneuploidy-induced cellular stress on the immune surveillance against aneuploid cells.
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http://dx.doi.org/10.1016/j.devcel.2018.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529225PMC
February 2018

Aneuploidy as a cause of impaired chromatin silencing and mating-type specification in budding yeast.

Elife 2017 08 25;6. Epub 2017 Aug 25.

Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United States.

Aneuploidy and epigenetic alterations have long been associated with carcinogenesis, but it was unknown whether aneuploidy could disrupt the epigenetic states required for cellular differentiation. In this study, we found that ~3% of random aneuploid karyotypes in yeast disrupt the stable inheritance of silenced chromatin during cell proliferation. Karyotype analysis revealed that this phenotype was significantly correlated with gains of chromosomes III and X. Chromosome X disomy alone was sufficient to disrupt chromatin silencing and yeast mating-type identity as indicated by a lack of growth response to pheromone. The silencing defect was not limited to cryptic mating type loci and was associated with broad changes in histone modifications and chromatin localization of Sir2 histone deacetylase. The chromatin-silencing defect of disome X can be partially recapitulated by an extra copy of several genes on chromosome X. These results suggest that aneuploidy can directly cause epigenetic instability and disrupt cellular differentiation.
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http://dx.doi.org/10.7554/eLife.27991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779231PMC
August 2017

Targeting the adaptability of heterogeneous aneuploids.

Cell 2015 Feb;160(4):771-784

Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MO 64110, USA; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. Electronic address:

Aneuploid genomes, characterized by unbalanced chromosome stoichiometry (karyotype), are associated with cancer malignancy and drug resistance of pathogenic fungi. The phenotypic diversity resulting from karyotypic diversity endows the cell population with superior adaptability. We show here, using a combination of experimental data and a general stochastic model, that the degree of phenotypic variation, thus evolvability, escalates with the degree of overall growth suppression. Such scaling likely explains the challenge of treating aneuploidy diseases with a single stress-inducing agent. Instead, we propose the design of an "evolutionary trap" (ET) targeting both karyotypic diversity and fitness. This strategy entails a selective condition "channeling" a karyotypically divergent population into one with a predominant and predictably drugable karyotypic feature. We provide a proof-of-principle case in budding yeast and demonstrate the potential efficacy of this strategy toward aneuploidy-based azole resistance in Candida albicans. By analyzing existing pharmacogenomics data, we propose the potential design of an ET against glioblastoma.
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http://dx.doi.org/10.1016/j.cell.2015.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328141PMC
February 2015

Origin replication complex binding, nucleosome depletion patterns, and a primary sequence motif can predict origins of replication in a genome with epigenetic centromeres.

mBio 2014 Sep 2;5(5):e01703-14. Epub 2014 Sep 2.

Unlabelled: Origins of DNA replication are key genetic elements, yet their identification remains elusive in most organisms. In previous work, we found that centromeres contain origins of replication (ORIs) that are determined epigenetically in the pathogenic yeast Candida albicans. In this study, we used origin recognition complex (ORC) binding and nucleosome occupancy patterns in Saccharomyces cerevisiae and Kluyveromyces lactis to train a machine learning algorithm to predict the position of active arm (noncentromeric) origins in the C. albicans genome. The model identified bona fide active origins as determined by the presence of replication intermediates on nondenaturing two-dimensional (2D) gels. Importantly, these origins function at their native chromosomal loci and also as autonomously replicating sequences (ARSs) on a linear plasmid. A "mini-ARS screen" identified at least one and often two ARS regions of ≥100 bp within each bona fide origin. Furthermore, a 15-bp AC-rich consensus motif was associated with the predicted origins and conferred autonomous replicating activity to the mini-ARSs. Thus, while centromeres and the origins associated with them are epigenetic, arm origins are dependent upon critical DNA features, such as a binding site for ORC and a propensity for nucleosome exclusion.

Importance: DNA replication machinery is highly conserved, yet the definition of exactly what specifies a replication origin differs in different species. Here, we utilized computational genomics to predict origin locations in Candida albicans by combining locations of binding sites for the conserved origin replication complex, necessary for replication initiation, together with chromatin organization patterns. We identified predicted sequences that exhibited bona fide origin function and developed a linear plasmid assay to delimit the DNA fragments necessary for origin function. Additionally, we found that a short AC-rich motif, which is enriched in predicted origins, is required for origin function. Thus, we demonstrated a new machine learning paradigm for identification of potential origins from a genome with no prior information. Furthermore, this work suggests that C. albicans has two different types of origins: "hard-wired" arm origins that rely upon specific sequence motifs and "epigenetic" centromeric origins that are recruited to kinetochores in a sequence-independent manner.
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http://dx.doi.org/10.1128/mBio.01703-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173791PMC
September 2014

Direct monitoring of the strand passage reaction of DNA topoisomerase II triggers checkpoint activation.

PLoS Genet 2013 3;9(10):e1003832. Epub 2013 Oct 3.

Department of Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, Minnesota, United States of America.

By necessity, the ancient activity of type II topoisomerases co-evolved with the double-helical structure of DNA, at least in organisms with circular genomes. In humans, the strand passage reaction of DNA topoisomerase II (Topo II) is the target of several major classes of cancer drugs which both poison Topo II and activate cell cycle checkpoint controls. It is important to know the cellular effects of molecules that target Topo II, but the mechanisms of checkpoint activation that respond to Topo II dysfunction are not well understood. Here, we provide evidence that a checkpoint mechanism monitors the strand passage reaction of Topo II. In contrast, cells do not become checkpoint arrested in the presence of the aberrant DNA topologies, such as hyper-catenation, that arise in the absence of Topo II activity. An overall reduction in Topo II activity (i.e. slow strand passage cycles) does not activate the checkpoint, but specific defects in the T-segment transit step of the strand passage reaction do induce a cell cycle delay. Furthermore, the cell cycle delay depends on the divergent and catalytically inert C-terminal region of Topo II, indicating that transmission of a checkpoint signal may occur via the C-terminus. Other, well characterized, mitotic checkpoints detect DNA lesions or monitor unattached kinetochores; these defects arise via failures in a variety of cell processes. In contrast, we have described the first example of a distinct category of checkpoint mechanism that monitors the catalytic cycle of a single specific enzyme in order to determine when chromosome segregation can proceed faithfully.
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http://dx.doi.org/10.1371/journal.pgen.1003832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789831PMC
March 2014

Epigenetically-inherited centromere and neocentromere DNA replicates earliest in S-phase.

PLoS Genet 2010 Aug 19;6(8):e1001068. Epub 2010 Aug 19.

Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.

Eukaryotic centromeres are maintained at specific chromosomal sites over many generations. In the budding yeast Saccharomyces cerevisiae, centromeres are genetic elements defined by a DNA sequence that is both necessary and sufficient for function; whereas, in most other eukaryotes, centromeres are maintained by poorly characterized epigenetic mechanisms in which DNA has a less definitive role. Here we use the pathogenic yeast Candida albicans as a model organism to study the DNA replication properties of centromeric DNA. By determining the genome-wide replication timing program of the C. albicans genome, we discovered that each centromere is associated with a replication origin that is the first to fire on its respective chromosome. Importantly, epigenetic formation of new ectopic centromeres (neocentromeres) was accompanied by shifts in replication timing, such that a neocentromere became the first to replicate and became associated with origin recognition complex (ORC) components. Furthermore, changing the level of the centromere-specific histone H3 isoform led to a concomitant change in levels of ORC association with centromere regions, further supporting the idea that centromere proteins determine origin activity. Finally, analysis of centromere-associated DNA revealed a replication-dependent sequence pattern characteristic of constitutively active replication origins. This strand-biased pattern is conserved, together with centromere position, among related strains and species, in a manner independent of primary DNA sequence. Thus, inheritance of centromere position is correlated with a constitutively active origin of replication that fires at a distinct early time. We suggest a model in which the distinct timing of DNA replication serves as an epigenetic mechanism for the inheritance of centromere position.
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http://dx.doi.org/10.1371/journal.pgen.1001068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924309PMC
August 2010

Determinants of Rad21 localization at the centrosome in human cells.

Cell Cycle 2010 May 15;9(9):1759-63. Epub 2010 May 15.

Department of Genetics, Cell Biology & Development, University of Minnesota Medical School, Minneapolis, MN, USA.

Cohesin proteins help maintain the physical associations between sister chromatids that arise in S-phase and are removed in anaphase. Recent studies found that cohesins also localize to the centrosomes, the organelles that organize the mitotic bipolar spindle. We find that the cohesin protein Rad21 localizes to centrosomes in a manner that is dependent upon known regulators of sister chromatid cohesion as well as regulators of centrosome function. These data suggest that Rad21 functions at the centrosome and that the regulators of Rad21 coordinate the centrosome and chromosomal functions of cohesin.
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http://dx.doi.org/10.4161/cc.9.9.11523DOI Listing
May 2010

Rad21 is required for centrosome integrity in human cells independently of its role in chromosome cohesion.

Cell Cycle 2010 May 15;9(9):1774-80. Epub 2010 May 15.

Department of Genetics, Cell Biology & Development, University of Minnesota Medical School, Minneapolis, MN, USA.

Classically, chromosomal functions in DNA repair and sister chromatid association have been assigned to the cohesin proteins. More recent studies have provided evidence that cohesins also localize to the centrosomes, which organize the bipolar spindle during mitosis. Depletion of cohesin proteins is associated with multi-polar mitosis in which spindle pole integrity is compromised. However, the spindle pole defects after cohesin depletion could be an indirect consequence of a chromosomal cohesion defect which might impact centrosome integrity via alterations to the spindle microtubule network. Here we show that the cohesin Rad21 is required for centrosome integrity independently of its role as a chromosomal cohesin. Thus, Rad21 may promote accurate chromosome transmission not only by virtue of its function as a chromosomal cohesin, but also because it is required for centrosome function.
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http://dx.doi.org/10.4161/cc.9.9.11524DOI Listing
May 2010

Direct interaction between Utp8p and Utp9p contributes to rRNA processing in budding yeast.

Biochem Biophys Res Commun 2010 Mar 6;393(2):297-302. Epub 2010 Feb 6.

Department of Microbiology, National Taiwan University, Taipei, Taiwan.

The small subunit (SSU) processome is an evolutionarily conserved ribonucleoprotein (RNP) complex that consists of U3 snoRNA and at least 40 protein components. The SSU processome is required for the generation of 18S rRNA in the budding yeast Saccharomyces cerevisiae. In this study we demonstrate that two essential components of the SSU processome, Utp8p and Utp9p, must interact directly for the SSU processome to function properly. Disruption of the Utp8p-Utp9p interaction by mutation of the respective interacting domain led to a compromised ability of yeast cells to process 35S pre-rRNA into 18S pre-rRNA. Loss of the Utp8p-Utp9p interaction also led to a decrease in the amount of Utp8p that interacted with U3 small nucleolar RNAs (snoRNAs) but did not affect the amount of Utp9p bound to U3 snoRNA, suggesting that Utp8p associates with the SSU processome by virtue of its interaction with Utp9p. Together, our data support a model where Utp8p and Utp9p must interact directly and functionally in the U3-containing SSU processome for optimal rRNA biosynthesis to occur in budding yeast.
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http://dx.doi.org/10.1016/j.bbrc.2010.02.003DOI Listing
March 2010

Rapid Cdc13 turnover and telomere length homeostasis are controlled by Cdk1-mediated phosphorylation of Cdc13.

Nucleic Acids Res 2009 Jun 9;37(11):3602-11. Epub 2009 Apr 9.

Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Budding yeast telomerase is mainly activated by Tel1/Mec1 (yeast ATM/ATR) on Cdc13 from late S to G2 phase of the cell cycle. Here, we demonstrated that the telomerase-recruitment domain of Cdc13 is also phosphorylated by Cdk1 at the same cell cycle stage as the Tel1/Mec1-dependent regulation. Phosphor-specific gel analysis demonstrated that Cdk1 phosphorylates residues 308 and 336 of Cdc13. The residue T308 of Cdc13 is critical for efficient Mec1-mediated S306 phosphorylation in vitro. Phenotypic analysis in vivo revealed that the mutations in the Cdc13 S/TP motifs phosphorylated by Cdk1 caused cell cycle delay and telomere shortening and these phenotypes could be partially restored by the replacement with a negative charge residue. In the absence of Ku or Tel1, Cdk1-mediated phosphorylation of Cdc13 showed no effect on telomere length maintenance. Moreover, this Cdk1-mediated phosphorylation was required to promote the regular turnover of Cdc13. Together these results demonstrate that Cdk1 phosphorylates the telomerase recruitment domain of Cdc13, thereby preserves optimal function and expression level of Cdc13 for precise telomere replication and cell cycle progression.
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http://dx.doi.org/10.1093/nar/gkp235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699520PMC
June 2009

Involvement of topoisomerase III in telomere-telomere recombination.

J Biol Chem 2006 May 16;281(19):13717-13723. Epub 2006 Mar 16.

Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei 10018, Taiwan; Institute of Internal Medicine, National Taiwan University Hospital, Taipei 10018, Taiwan. Electronic address:

Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of telomerase. In both mammalian tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative (ALT) recombination mechanism. In yeast, Sgs1p and its associated type IA topoisomerase, Top3p, may work coordinately in removing Holliday junction intermediates from a crossover-producing recombination pathway. Previous studies have also indicated that Sgs1 helicase acts in a telomere recombination pathway. Here we show that topoisomerase III is involved in telomere-telomere recombination. The recovery of telomere recombination-dependent survivors in a telomerase-minus yeast strain was dependent on Top3p catalytic activity. Moreover, the RIF1 and RIF2 genes are required for the establishment of TOP3/SGS1-dependent telomere-telomere recombination. In human Saos-2 ALT cells, human topoisomerase IIIalpha (hTOP3alpha) also contributes to telomere recombination. Strikingly, the telomerase activity is clearly enhanced in surviving si-hTOP3alpha Saos-2 ALT cells. Altogether, the present results suggest a potential role for hTOP3alpha in dissociating telomeric structures in telomerase-deficient cells, providing therapeutic implications in human tumors.
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http://dx.doi.org/10.1074/jbc.M600649200DOI Listing
May 2006

Telomere configuration influences the choice of telomere maintenance pathways.

Biochem Biophys Res Commun 2006 May 13;343(2):459-66. Epub 2006 Mar 13.

Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, ROC.

Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of telomerase. In yeast cells that lack telomerase, telomeres are maintained by alternative type I and type II recombination mechanisms. Previous studies identified several proteins to control the choice between two types of recombinations. Here, we demonstrate that configuration of telomeres also plays a role to determine the fate of telomere replication in progeny. When diploid yeasts from mating equip with a specific type of telomeric structure in their genomes, they prefer to maintain this type of telomere replication in their descendants. While inherited telomere structure is easier to be utilized in progeny at the beginning stage, the telomeres in type I diploids can gradually switch to the type II cells in liquid culture. Importantly, the TLC1/tlc1 yeast cells develop type II survivors suggesting that haploid insufficiency of telomerase RNA component, which is similar to a type of dyskeratosis congenital in human. Altogether, our results suggest that both protein factors and substrate availability contribute to the choice among telomere replication pathways in yeast.
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http://dx.doi.org/10.1016/j.bbrc.2006.03.011DOI Listing
May 2006