Assistant Professor of Biochemistry & Molecular Biology
215-762-4825
eishi.noguchi@drexelmed.edu

Education:
Ph.D. (1997) Molecular Biology, Kyushu University
Postdoctoral research 2000-2004, The Scripps Research Institute
 
Noguchi Lab Page

Research Program

Genetic instability is a major factor in the development of many diseases, most notably cancer. Many agents that cause genetic instability do so by interfering with DNA replication. This is when the DNA replication checkpoint control steps in to delay mitosis and control DNA replication, repair and recombination. This surveillance system ensures the high-fidelity transmission of genetic information from parents to offspring. A failure in this checkpoint pathway can lead to genetic instability and contribute to cancer development, but at the same time, checkpoints probably play a major role in the survival of cancer cells when they are treated with DNA damaging agents. In fact, inhibition of checkpoint proteins in tumor cells may be an efficient strategy to induce cell death specifically in cancer cells. Therefore, checkpoint proteins are thought to be potentially useful targets of anti-cancer agents.

The DNA replication checkpoint stabilizes replication forks that have stalled at DNA adducts and other lesions that block DNA polymerases. In the absence of the DNA replication checkpoint, stalled forks are thought to collapse, creating double strand breaks that threaten genome stability and cell viability. Therefore, discovering how cells cope with replication fork arrest is essential for understanding the mechanisms of genome maintenance. We recently found Swi1/Timeless and Swi3/Tipin proteins form a replication protection complex (FPC) that is required for stabilization of replication forks and for effective activation of replication checkpoint kinase Chk2/Cds1. Since replication fork collapse during DNA replication is one of the most serious threats causing genetic instability, proteins involved in replication fork stabilization should be one of major targets of anti-cancer drugs. Therefore it is essential to find the network of proteins involved in replication fork stabilization. To pursue this aim, we employ the fission yeast Schizosaccharomyces pombe and mammalian cell culture as model systems. We have isolated Swi1-Swi3 interacting proteins by biochemical and genetic strategies, including protein purification, screening of synthetic lethal mutations and two-hybrid screening. These investigations have identified the protein network involved in replication fork stabilization. We will characterize these proteins to understand the detailed mechanisms of replication fork maintenance and checkpoint signaling. Maintenance of replication forks during S-phase is crucial for cell survival and is required for efficient transduction of checkpoint signaling. Therefore, the investigation of the protein network involved in stabilization of replication forks will provide novel and important insights into genome maintenance mechanism in humans, since they directly have an impact on cancer biology.

Selected references:

Noguchi C, Garabedian M, Malik M, and Noguchi E. (2008) A vector system for genomic FLAG tagging in Schizosaccharomyces pombe. Biotechnology Journal, in press (Published online, Aug 26, DOI: 10.1002/biot.200800140).

Eishi Noguchi, Alison B. Ansbach, Chiaki Noguchi and Paul Russell. (2008) Assays used to study replication checkpoints. Methods in Molecular Biology, in press.

Jordan B. Rapp, Alison B. Ansbach, Chiaki Noguchi and Eishi Noguchi. (2008) ChIP of replication factors moving with the replication forks. Methods in Molecular Biology, in press.

Ansbach AB, Noguchi C, Klansek IW, Heidlebaugh M, Nakamura TM, Noguchi E.
(2008) RFCCtf18 and the Swi1-Swi3 complex function in separate and redundant pathways required for the stabilization of replication forks to facilitate sister chromatid cohesion in Schizosaccharomyces pombe.
Mol. Biol. Cell, 19: 595-607.

Noguchi C, Noguchi E. (2007) Sap1 promotes the association of the replication fork protection complex with chromatin and is involved in the replication checkpoint in Schizosaccharomyces pombe. Genetics, 175:553-566.

Coulon S, Noguchi E, Noguchi C, Du L-L, Nakamura MT, Russell P.
(2006) Rad22Rad52-Dependent Repair of Ribosomal DNA Repeats Cleaved by Slx1-Slx4 Endonuclease.
Mol. Biol. Cell. 17:2081-90.

Matsumoto S, Ogino K, Noguchi E, Russell P, Masai H.
(2005) Hsk1-Dfp1/Him1, the Cdc7-Dbf4 kinase in Schizosaccharomyces pombe, associates with Swi1, a component of the replication fork protection complex.
J. Biol. Chem. 280: 42536-442542.

Noguchi E, Noguchi C, McDonald WH, Yates III JR, Russell P. (2004) Swi1 and Swi3 are components of a replication fork protection complex in fission yeast. Mol. Cell. Biol. 24: 8342-8355.



Zhao H, Tanaka K, Noguchi E, Noguchi C, Russell P. (2003) Replication checkpoint protein Mrc1 is regulated by Rad3 and Tel1 in fission yeast. Mol. Cell. Biol. 23: 8395-8403. 



Noguchi E, Noguchi C, Du L-L, Russell P. (2003) Swi1 prevents replication fork collapse and controls checkpoint kinase Cds1. Mol. Cell. Biol. 23: 7861-7874. 



Gaillard PH, Noguchi E, Shanahan P, and Russell P. (2003) The endogenous Mus81-Eme1 complex resolves Holliday Junctions by a nick and counter nick mechanism. Mol. Cell 12: 747-759. 



Boddy MN, Shanahan P, McDonald WH, Lopez-Girona A, Noguchi E, Yates III JR, Russell P. (2003) Replication checkpoint kinase Cds1 regulates recombinational repair protein Rad60. Mol. Cell. Biol.23:5939-5946.



Noguchi E, Shanahan P, Noguchi C, Russell P. (2002) CDK phosphorylation of Drc1 regulates DNA replication in fission yeast. Current Biology 12: 599-605.