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Tye, Bik-Kwoon
Cornell Faculty Member
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- biochemistry
- bioinformatics
- biomedical sciences
- breast cancer
- cancer research
- cell biology
- computational biology
- genetics
- genomics
- insects
- microbiology
- molecular biology
- molecular genetics
- new life sciences
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Research
research overview
- DNA replication occurs only once in each mitotic cell cycle. Tampering of the molecular mechanisms that impose this strict regulation may lead to genetic instability, apoptosis, and cancer. Using yeast as a model organism, we have taken several very different approaches to address how this strict regulation at the initiation step is evolved and the consequence of tampering with replication fork progression. 1. The evolution of replication origins by comparative functional genomics The replication machinery for the initiation of DNA synthesis is well conserved from yeast to human, yet the sites at which the pre-replication complex assembles appear to have diverged significantly between organisms as well as between initiation sites within the same organism. Replication origins of Saccharomyces cerevisiae are defined sequences of about 100 bp that include a 17 bp essential element known as ARS consensus sequence (ACS) where the origin recognition complex binds. Replication origins of fission yeast are much larger and less well defined. In mammals, replication initiation occurs in zones that require the support of sequences as large as 50 kb. To better understand the constituents of a replication origin, we have taken a comparative functional genomics approach to analyze replication origins isolated from different yeastspecies evolved pre or post genome duplication. This approach allows us to address a number of probing questions such as: 1. How are the ACSs of related yeastspecies different? 2. How do the replication initiation machineries of the related yeast species co-evolve with their respective ACSs? 3. What are the additional essential elements for ARS function? 4. Is there conservation in genomic locations for ARS function and what is the evolutionary pressure? 5. Does a phylogenetic tree derived from functional relatedness of ARSs bear any resemblance to the phylogenetic tree derived from genome sequence relatedness? Investigator: Dr. Ivan Liachko Collaborator: Dr. Uri Keich, Dept of Computer Science 2. Molecular mechanisms for the predisposition to cancer by a defect in replication elongation Genomic instability (GIN) and chromosome aneuploidy are hallmarks of cancer cells, however their sources and functions in tumorigenesis are unclear. DNA replication stress is a distinctive feature of uncontrolled cell proliferation yet a causative relationship between DNA replication defects and cancer has not been established. The F345I allele of Mcm4, which encodes a subunit of the hexameric MCM helicase, induces a high incidence (>80%) of mammary adenocarcinomas in homozygous female mice. Homozygous diploid yeast carrying the equivalent point mutation (mcm4Chaos3) are predisposed to genome instability and accelerated proliferation as well as other characteristics of cancer cells including gross chromosome rearrangements. Interestingly, haploid mutants are not predisposed to these growth states or characteristics. We will use the yeast model to address fundamental problems of tumor progression and target specificity in cancer biology. Specifically, we are investigating the mechanisms by which a defect in the replicative helicase lead to accelerated proliferation, a universal characteristic of cancer cells. We are also investigating the basis for the distinctive responses of haploid and diploid cells to the mcm4Chaos3 mutation that predisposes one of these cell types to cancer-like properties. Investigator: Xin Li Collaborator: Dr. John Schimenti 3. Organization and structure of the replication fork complex The unfaltering progression of every replication fork is vital to the successful duplication of the genome. Mcm10 is a critical component of the replication fork in coupling the MCM helicase with the elongation machinery. Using Mcm10 as an entry point, we are studying the structure and organization of the fork complex by genetic and biochemical approaches. We have identified genetic interactors of Mcm10 by suppressor analysis and functional interactors of Mcm10 by conventional biochemistry and in vitro reconstitution studies. Our goal is to elucidate the process of assembly of the replication fork complex. Investigators: Dr. Manhee Suh and Chanmi Lee Collaborator: Dr. Shlomo Eisenberg of University of Connecticut, Qiuyue Yang and Quan Hao of MacCHESS.
research activities
area(s) of concentration/expertise
keywords
- DNA replication; S phase checkpoint; replication fork integrity; genome stability;
submitted impact statement
Publications
individual publications
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academic article
- A Comprehensive Genome-Wide Map of Autonomously Replicating Sequences in a Naive Genome. PLoS Genetics. 6. 2010
- Alternative Mechanisms for Coordinating Polymerase alpha and MCM Helicase. Molecular and Cellular Biology. 30:423-435. 2010
- Old-Fashioned Genetics Screens Give New Insights to DNA Replication. Cell Cycle. 9:4610-4611. 2010
- Aneuploidy and Improved Growth are Coincident but Not Causal in a Yeast Cancer Model. PLoS Biology. 7. 2009
- Mcm10 mediates the interaction between DNA replication and silencing machineries. Genetics. 181:379-391. 2009
- Novel DNA-Binding Properties of the MCM10 Protein from Saccharomyces Cerevisiae. Journal of Biological Chemistry. :25412-25420. 2009
- Computational detection of significant variation in binding affinity across two sets of sequences with application to the analysis of replication origins in yeast. BMC Bioinformatics. 9:372. 2008
- A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Natural Genetics. 39:93-98. 2007
- Genome-Wide Hierarchy of Replication Origin Usage in Saccharomyces cerevisiae. PLoS Genetics. 2. 2006
- Mcm10 is required for the maintenance of transcriptional silencing in Saccharomyces cerevisiae. Genetics. 171:503-515. 2005
- Dual functional regulators coordinate DNA replication and gene expression in proliferating cells. Front. Biosci. 9:2548-2555. 2004
- Mcm1 promotes replication initiation by binding specific elements at replication origins. Molecular and Cellular Biology. 24:6514-6524. 2004
- Mcm10 and Cdc45 cooperate in origin activation in Saccharomyces cerevisiae. J Mol Biol. 340:195-202. 2004
- Drosophila Mcm10 interacts with members of the pre-replication complex and is required for proper chromosome condensation. Molecular Biology of the Cell. 14:2206-2215. 2003
- Evidence for a role of MCM5 in transcriptional repression of sub-telomeric and Ty-proximal genes in S. cerevisiae. Journal of Biological Chemistry. 278:27372-27381. 2003
- Mcm1 binds replication origins. Journal of Biological Chemistry. 278:6093-6100. 2003
- Mcm7, a subunit of the presumed MCM helicase, modulates its own expression in conjunction with Mcm1. Journal of Biological Chemistry. 278:25408-25416. 2003
- The budding yeast mcm10/dna43 mutant requires a novel DNA repair pathway for viability. Genes Cells. 8:465-480. 2003
- Mcm3p is polyubiquitinated during mitosis before the establishment of the pre-replication complex. Journal of Biological Chemistry. 277:41706-41714. 2002
- The Methanobacterium thermoautotrophicum MCM protein forms heptameric rings. EMBO Reports. 3:792-797. 2002
- Two mcm3 mutations affect different steps in the initiation of DNA replication. Journal of Biological Chemistry. 277:30824-30831. 2002
- Mcm10 and the MCM2-7 complex interact to initiate DNA synthesis and to release replication factors from origins. Genes & Development. 14:913-926. 2000
- Mcm1 regulates the recombination enhancer controlling donor preference in Saccharomyces mating-type switching. Genes & Development. 12:1726-1737. 1998
- A lesion in the DNA replication initiation factor Mcm10 induces pausing of elongation forks through chromosomal replication origins in S. cerevisiae. Molecular and Cellular Biology. 17:3261-3271. 1997
- Mcm2 and Mcm3 are constitutive nuclear proteins that exhibit distinct isoforms and bind chromatin during specific cell cycle stages of S. cerevisiae. Molecular Biology of the Cell. 8:1587-1601. 1997
- Mcm2 is a target of regulation by Cdc7-Dbf4 during the initiation of DNA synthesis in S. cerevisiae. Genes & Dev. 11:3365-3374. 1997
- Nuclear accumulation of S. cerevisiae Mcm3 is dependent on its nuclear localization sequence. Genes to Cells. 2:631-643. 1997
- MCM proteins, their physical interactions and dosage effects on DNA replication in yeast. Molecular and Cellular Biology. 16:5081-5090. 1996
- The yeast MCM1 protein is regulated post-transcriptionally by the flux of glycolysis. Molecular and Cellular Biology. 15:4631-4639. 1995
- Cell cycle-regulated nuclear localization of MCM2 and MCM3 which are required for the initiation of DNA synthesis at chromosomal replication origin in yeast. Genes & Development. 7:2149-2160. 1993
- Identification and characterization of a nuclease activity specific for G4 tetrastranded DNA. Proceedings at the National Academy of Science USA. 90:3157-3161. 1993
- CDC46/MCM5, a yeast protein whose subcellular localization is cell cycle-regulated, is involved in DNA replication at autonomously replicating sequences. Proceedings at the National Academy of Science USA. 89:10459-10463. 1992
- Chromosome loss, hyperrecombination, and cell cycle arrest in a yeast mcm1 mutant. Molecular Biology of the Cell. 3:971-980. 1992
- A yeast protein that binds to vertebrate telomeres and conserved telomeric junctions in yeast. Genes & Development. 5:49-59. 1991
- Both Activation and Repression of a-Specific Genes in Yeast Require Mcm1. Proceedings at the National Academy of Science USA. 88:10966-10970. 1991
- Functional domains of the yeast transcription/replication factor MCM1. Genes & Development. 5:751-763. 1991
- Mcm2 and Mcm3, two proteins important for ARS activity are related in structure and function. Genes & Development. 5:944-957. 1991
- The phenotype of the minichromosome maintenance mutant mcm3 is characteristic of mutants defective in DNA replication. Molecular and Cellular Biology. 10:5707-5720. 1990
- A protein involved in minichromosome maintenance in yeast binds a transcriptional enhancer conserved in eukaryotes. Genes & Development. 3:921-935. 1989
- The OBF1 protein and its DNA-binding site are important for the function of an autonomously replicating sequence in Saccharomyces cerevisiae. Molecular and Cellular Biology. 9:2906-2913. 1989
- A Saccharomyces cerevisiae protein involved in plasmid maintenance is necessary for mating of MATα cells. J. Mol. Biol. 204:593-606. 1988
- Meiotic disjunction of homologues in S. cerevisiae is directed by pairing and recombination of the chromosome arms but not by pairing of the centromeres. Genetics. 119:273-287. 1988
- Specific interaction between a Saccharomyces cerevisiae protein and a DNA element associated with certain autonomously replicating sequences. Proceedings at the National Academy of Science USA. 85:743-746. 1988
- A mutant which affects the function of autonomously replicating sequences in yeast. J. Mol. Biol. 192:805-814. 1986
- Identification of a telomere–binding activity from yeast. Proceedings at the National Academy of Science USA. 86:3713-3717. 1986
- The mitotic stability of deletion derivatives of chromosome III in yeast. Proceedings at the National Academy of Science USA. 83:414-418. 1986
- Construction of telocentric chromosomes in yeast. Proceedings at the National Academy of Science USA. 82:2106-2110. 1985
- Resolution of dicentric chromosomes via ty–mediated recombination. Genetics. 110:397-419. 1985
- Isolation and characterization of the centromere from chromosome V (CEN5) of Saccharomyces cerevisiae. Molecular and Cellular Biology. 4:86-91. 1984
- Mutants of S. cerevisiae defective in the maintenance of minichromosomes. Genetics. 106:365-385. 1984
- Unusual DNA sequences associated with the ends of yeast chromosomes. Nature. 310:157-160. 1984
- A family of S. cerevisiae repetitive autonomously replicating sequences that have very similar genomic environments. J. Mol. Biol. 168:505-523. 1983
- Organization of DNA sequences and replication origins at yeast telomeres. Cell. 33:563-573. 1983
- Autonomously replicating sequences in Saccharomyces cerevisiae. Proceedings at the National Academy of Science USA. 77:6329-6333. 1980
- Excision repair of uracil during replication of fX174 DNA in vitro. Biochem. Biophys. Res. Comm. 82:434-441. 1978
- Uracil incorporation: A source of pulse–labeled DNA fragments in the replication of E. coli chromosome. Proceedings at the National Academy of Science USA. 75:233-237. 1978
- Excision–repair of uracil incorporated in DNA as a result of a defect in dUTPase. J. Mol. Biol. 117:293-306. 1977
- Transient accumulation of Okazaki fragments as a result of uracil incorporation into nascent DNA. Proceedings at the National Academy of Science USA. 74:154-157. 1977
- A mutant of phage P22 with randomly permuted DNA. J. Mol. Biol. 100:421-426. 1976
- Mutagenesis by insertion of a drug–resistance element carrying an inverted repetition. J. Mol. Biol. 97:561-575. 1975
- Alignment of partial denaturation maps of circular permuted DNA by computer. J. Mol. Biol. 85:528-532. 1974
- Non–random circular permutation of phage P22 DNA. J. Mol. Biol. 85:501-527. 1974
- Packaging of an oversize transducing genome by Salmonella phage P22. J. Mol. Biol. 85:485-500. 1974
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book
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conference paper
- CDC46/MCM5, a yeast protein whose subcellular localization is cell cycle-regulated, is involved in DNA replication at autonomously replicating sequences. Proc. Natl. Acad. Sci. USA. 10459-10463. 1992
- Both Activation and Repression of a-Specific Genes in Yeast Require Mcm1. Proc. Natl. Acad. Sci. USA. 10966-10970. 1991
- Specific interaction between a Saccharomyces cerevisiae protein and a DNA element associated with certain autonomously replicating sequences. Proc. Natl. Acad. Sci. USA. 1988
- Complexity of the enzyme system for the initiation of DNA replication in yeast. ICN–UCLA Symposia on Molecular and Cellular Biology. 1987
- Identification of an ARS–binding protein in Saccharomyces cerevisiae. ICN–UCLA Symposia on Molecular and Cellular Biology. 1987
- Identification of a telomere–binding activity from yeast. Proc. Natl. Acad. Sci. USA. 3713-3717. 1986
- The mitotic stability of deletion derivatives of chromosome III in yeast. Proc. Natl. Acad. Sci. USA. 1986
- Construction of telocentric chromosomes in yeast. Proc. Natl. Acad. Sci. USA. 2106-2110. 1985
- Regulation of DNA replication initiation in yeast. Yeast Cell Biology. UCLA Symposia on Molecular and Cellular Biology. 1985
- Functional components of the Saccharomyces cerevisiae chromosomes –– replication origins and centromeric sequences. Structure and DNA–Protein Interactions of Replication Origins. ICN–UCLA Symposia on Molecular and Cellular Biology. 1981
- Autonomously replicating sequences in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA. 6329-6333. 1980
- Complexity of chromosomal replication origins in Saccharomyces cerevisiae. Mechanistic Studies of DNA Replication and Genetic Recombination. ICN–UCLA Symposia on Molecular and Cellular Biology. 1980
- Excision–repair of uracil in DNA: Its implications for the discontinuous replication of DNA in vivo and in vitro. Cold Spring Harbor Symposia on Quantitative Biology. 1979
- Uracil incorporation: A source of pulse–labeled DNA fragments in the replication of E. coli chromosome. Proc. Natl. Acad. Sci. USA. 233-237. 1978
- Transient accumulation of Okazaki fragments as a result of uracil incorporation into nascent DNA. Proc. Natl. Acad. Sci. USA. 154-157. 1977
- Dual functional regulators coordinate DNA replication and gene expression in proliferating cells 2004
- Initiating DNA synthesis: from recruiting to activating the MCM complex 2001
- Insights into DNA replication from the third domain of life 2000
- The hexameric eukaryotic MCM helicase: building symmetry from nonidentical parts 2000
- Minichromosome maintenance as a genetic assay for defects in DNA replication 1999
- The MCM proteins in DNA Replication 1999
- The MCM2-3-5 protein family, are they replication licensing factors? 1994
- Workshop on Control Mechanisms of DNA Synthesis 1991
- Meiotic segregation of normal and deletion chromosomes in Saccharomyces cerevisiae 1988
- An agarose gel assay that permits detection of DNA binding proteins in yeast cell extracts. Recombinant DNA, Part F 1987
- Host factors in nuclear plasmid maintenance in Saccharomyces cerevisiae 1987
- Site–directed chromosomal rearrangements in yeast. Recombinant DNA, Part D 1987
- Hybridization with synthetic oligonucleotides 1979
- P22 morphogenesis II: Mechanism of DNA encapsulation 1974
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Teaching
teaching overview
- My major teaching commitment is BioBM332, principles of biochemistry. The objective of this course is to teach the fundamentals of modern biology. First and foremost, this course aims to prepare students to be informed citizens, but more specifically, to prepare them for advance courses in any area of biology at the molecular level, whether it is in developmental or behavioral biology, ecology or evolutionary biology, bioinformatics or technology based medical sciences. We learn about the chemistry, structure and functions of nucleic acids. We discuss their functions not just within the confines of a test tube but also within the environment of a cell. We learn about genomes, genes and gene products and how they relate to one another in the context of a cell.
teaching activities
Service
service to the profession
- Biology & Medicine Panel, Research Grants Council of Hong Kong Panel Member 2003 -
- NIH Molecular Genetics C Study Section Ad hoc panel member - 2008
- Panel for Eukaryotic Genetics, National Science Foundation Ad Hoc, Panel Member - 2006
- Science Advisory Committee for Hong Kong University of Science and Technology Chairperson 1996 - 2003
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Background
education and training
- Ph.D. in Microbiology, Massachusetts Institute of Technology 1974
- University of California, San Francisco 1971
- B.A. in Chemistry, Wellesley College 1969
awards and honors
- Helen Hay Whitney Fellow, 1974
- Whitney Fellowship, 1972
- Sloan Traineeship, 1971
- Wellesley Scholarship, 1966
Other
research keyword
- DNA replication; S phase checkpoint; replication fork integrity; genome stability;