Bik-Kwoon Tye
Professor of Molecular Biology

Bik Tye

Phone

607-255-2445

Address

Department of Molecular Biology & Genetics
325 Biotechnology Building
Cornell University
Ithaca, NY 14853-2703

Email

Web Sites

Department Profile

Background

Bik Tye is Professor of Molecular Biology & Genetics and Director of Graduate Studies of Genetics & Development. She received her A.B. from Wellesley College in 1969, her M.S. from the University of California, San Francisco in 1971 and her Ph.D. from the Massachusetts Institute of Technology in 1974. She was a Helen Hay Whitney Fellow at Stanford University School of Medicine prior to joining Cornell University as assistant professor in 1977.  She teaches BioBM332, Principles of Biochemistry & Molecular Biology.

Research Description

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.

Selected Publications

  • Click Click here  to view Dr. Tye's PubMed listings.