Research program:
Genomic instability is associated with cancer and aging. Problems during DNA replication can cause accumulation of mutations and chromosome rearrangements. Therefore, it is of high significance to understand the cellular programs that preserve genomic integrity during DNA replication. The replication machinery can collide with a number of natural obstacles on the chromosome, leading to replication fork arrest or breakage. These obstacles include DNA binding proteins such as the transcription machinery. In addition, DNA secondary structures generated at repeat DNA sequences and highly ordered chromatin structures can also cause replication problems. Therefore, our research focuses on how DNA is protected at the replication fork.
As a prelude to understand the mechanisms of replication fork maintenance, we have discovered two proteins, Swi1 and Swi3, which are localized at the replication fork in a model organism, the fission yeast Schizosaccharomyces pombe. Our investigation has revealed that the Swi1-Swi3 complex plays a critical role in proper DNA replication by protecting DNA replication fork structures, which in turn prevents genomic instability. Accordingly, we designated this complex the replication fork protection complex (FPC) (Noguchi et al, 2004). The functions of the FPC are conserved throughout evolution. We have found that the human FPC (Timeless-Tipin) also protects replication forks, contributing to stable inheritance of genomic DNA (Leman et al, 2010). During the course of our molecular and biochemical studies, we have found that FPC is involved in a variety of genome maintenance mechanisms at the replication forks. We showed FPC is required to coordinate sister chromatid cohesion with DNA replication (Ansbach et al, 2008, Leman et al, 2010, Rapp et al, 2010). We also found that FPC genetically interacts with proteins involved in chromatin organization (Noguchi and Noguchi, 2007, Garabedian et al, 2011).
To further understand the mechanisms of stable inheritance of the genome, we have currently investigating how chromatin structures at the replication fork affect proper DNA replication. The dynamic changes in chromatin structures are regulated by modifications of histone proteins, which play a key role in epigenetic inheritance of genetic information during DNA replication of the genome. Therefore, it is of significant importance to understand dynamics and roles of histone modifications during DNA replication. We have also set out on a research project toward understanding how telomere structures are maintained during DNA replication (Moser et al, 2009). It is widely known that premature aging syndromes are often associated with short telomeres, suggesting that proper length control and maintenance of telomeric DNA are essential for the development, growth, and timely death of eukaryotic cells. Chromatin remodeling and telomere maintenance are critical components of cellular genome maintenance during DNA replication. Therefore, our research projects will provide a framework for guiding investigations that will greatly impact the biology of cancer and aging.
Selected references:
"The double-bromodomain proteins Bdf1 and Bdf2 modulate chromatin structure to regulate S-phase stress response in Schizosaccharomyces pombe"
Garabedian MV, Noguchi C, Ziegler MA, Das MM, Singh T, Harper LJ, Leman AR, Khair L, Moser BA, Nakamura TM, Noguchi E*
Genetics, in press (2011).
"Division of labor of the replication fork protection complex subunits in sister chromatid cohesion and Chk1 activation"
Noguchi E*
Cell Cycle, 10(13): 2055-2056 (2011).
"Checkpoint-dependent and -independent roles of Swi3 in replication fork recovery and sister chromatid cohesion"
Rapp JB, Noguchi C, Das MM, Wong LK, Ansbach AB, Holmes AM, Arcangioli B, Noguchi E
PLoS ONE, 5(10): e13379 (2010).
"The DNA replication checkpoint and preserving genomic integrity during DNA synthesis"
Noguchi E
Nature Education, 3(9): 46 (2010).
"Human Timeless and Tipin stabilize replication forks and facilitate sister chromatid cohesion"
Leman AR, Noguchi C, Lee CY, Noguchi E
J. Cell Sci., 123: 660-670 (2009).
"Differential arrival of leading and lagging strand DNA polymerases at fission yeast telomeres"
Moser BA, Subramanian L, Chang YT, Noguchi C, Noguchi E, Nakamura TM
EMBO J., 810-820 (2009)
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"Assays used to study replication checkpoints"
Noguchi E, Ansbach AB, Noguchi C, Russell P
Methods in Molecular Biology, 521: 493-507 (2009).
"ChIP of replication factors moving with the replication fork"
Rapp JB, Ansbach AB, Noguchi C, Noguchi E
Methods in Molecular Biology, 521: 191-202 (2009).
"A vector system for genomic FLAG tagging in Schizosaccharomyces pombe"
Noguchi C, Garabedian M, Malik M, Noguchi E.
Biotechnology Journal, 3: 1280-1285 (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"
Ansbach AB, Noguchi C, Klansek IW, Heidlebaugh M, Nakamura TM, Noguchi E
Mol. Biol. Cell, 19: 595-607 (2008).
"Sap1 promotes the association of the replication fork protection complex with chromatin and is involved in the replication checkpoint in Schizosaccharomyces pombe"
Noguchi C, Noguchi E
Genetics, 175:553-566 (2007).
"Swi1 and Swi3 are components of a replication fork protection complex in fission yeast"
Noguchi E, Noguchi C, McDonald WH, Yates III JR, Russell P
Mol. Cell. Biol., 24: 8342-8355 (2004).
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