Toru Nakamura
Email Address: nakamut@uic.eduCollege: Medicine Department: Biochemistry and Molecular Genetics
Title: Professor
Office: 2202 MBRB M/C 669 Phone: 9961988
Webpage: https://nakamura.lab.uic.edu/
Participating in the Chancellor’s Undergraduate Research Awards program: Yes
Research Interest:
Our laboratory is interested in understanding how maintenance of telomeres, the natural ends of linear eukaryotic chromosomes, is regulated. Proper maintenance of telomeres is crucial for stable inheritance of the genome. Deregulation of telomere maintenance mechanisms has been found to be a key event in tumorigenesis, thus mechanistic insights on how various proteins collaborate to generate functional telomeres might lead to effective methods for preventing cancer. In addition, telomere maintenance defects have also been linked to pre-mature aging.
We use fission yeast Schizosaccharomyces pombe as a model system. Advantages of S. pombe include well-characterized DNA damage responses with high structural and functional conservation to mammalian cells, and amenability to genetic, biochemical and cytological studies. In addition, the ability of fission yeast to bypass the need for functional telomere maintenance mechanisms by circularizing all chromosomes provides flexibility, not available in any other organisms, in manipulating telomere related genes without being hindered by cell lethality. In fact, S. pombe cells lacking telomerase, as well as cells lacking both Tel1ATM and Rad3ATR checkpoint kinases survive telomere maintenance defects by circularizing all three chromosomes.
We have demonstrated by quantitative chromatin immunoprecipitation (ChIP) assays that the leading strand DNA polymerase (Pol ε) arrives to replicating telomeres significantly earlier than the lagging strand DNA polymerases (Pol α and Pol δ), and replicating telomeres strongly recruit Replication Protein A (RPA) and Rad3-Rad26 (ATR-ATRIP) complexes in fission yeast. We have also established the cell-cycle-regulated recruitment timing for MCM, Mre11-Rad50-Nbs1 (MRN) complex, Trt1 (TERT, catalytic subunit of telomerase), and telomere capping proteins (Pot1 and Stn1). In addition, we have established that Tel1ATM and Rad3ATR kinases are redundantly required to promote telomere protection and telomerase recruitment by promoting efficient recruitment of the telomere capping complex subunit Ccq1 to telomeres.
We have also discovered that Tel1ATM/Rad3ATR-dependent phosphorylation of Ccq1 on Thr93 is essential for telomerase association with telomeres, and that the 14-3-3-like domain of the telomerase regulatory subunit Est1 specifically recognizes and binds the phosphorylated Thr93 of Ccq1. Phosphorylation of Ccq1 is negatively regulated by the telomerase inhibitors Taz1, Rap1 and Poz1, and telomere elongation and increased telomerase association with telomeres found in rap1Δ cells are dependent on Ccq1 Thr93 phosphorylation. On the other hand, Ccq1 Thr93 phosphorylation is also increased as telomeres shorten in telomerase mutant cells. Taken together, we thus uncovered the Tel1ATM/Rad3ATR-dependent Ccq1-Est1 interaction as a critical regulatory mechanism that ensures stable maintenance of telomeres in fission yeast cells.
In terms of undergraduate student research, fission yeast cells represent an attractive system to get introduced to molecular genetics and biochemistry research since yeast is easy to handle and does not require extensive safety training before starting experiments.
Student should be majoring in area related to biochemistry, genetics and molecular biology. Brief Summary of what is expected from the student:
We are interested in students who show active interest in research topics of our lab. It would be useful if students are willing to read relevant research papers, and take initiative in designing and interpreting research projects.
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